Pyrimidine Derivative, Method For Preparing Same And Use Thereof In Medicine

ABSTRACT

The present invention relates to a pyrimidine derivative, a method for preparing same and use thereof in medicine. In particular, the present invention relates to a pyrimidine derivative represented by general formula (I), a method for preparing same and a pharmaceutically acceptable salt thereof as well as use thereof as a therapeutic agent, in particular as a FGFR4 kinase inhibitor, definitions of each substituent in the general formula (I) being the same as those defined in the description.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a divisional application of U.S. patentapplication Ser. No. 16/800,057 filed Feb. 25, 2020, which is adivisional application of U.S. patent application Ser. No. 16/302,310filed Nov. 16, 2018 and issued as U.S. Pat. No. 10,654,836 on May 19,2020, which is a national phase entry under 35 U.S.C. § 371 ofInternational Application No. PCT/CN2017/085135 filed May 19, 2017,which claims priority from Chinese Patent Application No. 201610341444.0filed May 20, 2016, all of which are hereby incorporated herein byreference.

TECHNICAL FIELD

The present invention relates to a novel pyrimidine derivative,preparation method thereof and a pharmaceutical composition containingthe derivative, and relates to the use thereof as a therapeutic agent,in particular as a FGFR4 inhibitor.

BACKGROUND ART

The fibroblast growth factor receptor (FGFR) family is composed of fourmembers (FGFR1, FGFR2, FGFR3, and FGFR4), which is a kinase belonging tothe receptor tyrosine kinase family, and the binding of FGF leads toFGFR dimerization, followed by autologous phosphorylation of receptorsand activation of downstream signaling pathways. Activation of receptorsis sufficient to regenerate and activate specific downstream signalingpartners involved in the regulation of diverse processes such as cellgrowth, cell metabolism, and cell survival. Therefore, the FGF/FGFRsignaling pathway has multiple effects in many critical cellularbiological processes such as tumor cell proliferation, migration,infiltration, and angiogenesis. The four members of the FGFR familydiffer from each other in terms of their ligand affinity and tissuedistribution. The genomic structure of the FGFR-4 gene contains 18exons.

Human FGF19 gene is located at 11q13.1, the specific binding of FGFR4 toits ligand FGF19 inhibits cell apoptosis and NF-kB signaling, andup-regulates expression of genes involved in cell proliferation;activation of FGFR4 may lead to a decrease in Ikkβ activity inTNF-α-treated cells, along with the reduction of NF-kB distribution incells, and attenuates the cell apoptotic effect. Four FGFR genes areexpressed in human liver, but mature hepatocyte only expresses FGFR4 inlarge amounts. The binding of FGFR4 to its ligand can also regulate themetabolism of bile acid. The balance of the conversion of cholesterol tobile acid in the body is closely related to various normal physiologicalfunctions of the body. Damage of this balance can cause variousdiseases, for example fatty liver and cardiovascular and cerebrovasculardiseases such as arteriosclerosis. Therefore, the interaction betweenFGFR4 and FGF19 has become a new target for cholesterol-lowering drugsin the treatment of diseases such as hyperlipidemia.

In recent years, more and more evidence indicates that there are geneamplification mutations of FGFR1, FGFR2, FGFR3 and FGFR4 in varioustypes of cancer. A large amount of evidence indicates that FGFR1 hasgene mutations in breast cancer, non-small cell lung cancer andglioblastoma, has fusion protein formation caused by gene transpositionin acute myeloid leukemia, and has over-expression in pancreatic cancer,bladder cancer, prostate cancer, and esophageal cancer; FGFR2 has genemutations and amplification in gastric cancer, breast cancer and uterinecancer, and has over-expression in prostate cancer, esophageal cancer,ovarian cancer, pancreatic cancer, brain tumor, and colorectal cancer;FGFR3 has gene mutations in multiple myeloma and bladder cancer, and hasover-expression in ovarian cancer, non-small cell lung cancer, andhepatocellular carcinoma; FGFR4 has gene mutations and over-expressionin lung cancer, ovarian cancer, prostate cancer, hepatocellularcarcinoma and cholangiocarcinoma etc., and also has over-expression inthyroid cancer, ovarian cancer, etc. (French et al. 2012 PLos ONE7(5):e367313; Sia et al. 2013 Gastroejterology 144:829-840).

A series of patents about FGFR inhibitor have been published, however,there are fewer patent disclosures on selective inhibition of FGFR4, andinhibitors selective for FGFR4 have less toxicity than FGFR inhibitors(Brown, A P et al (2005), Toxocol. Pathol., 449-455). FGFR4 inhibitorscurrently in clinical include FGF-401 (Novartis, clinical phase II),BLU-554 (Blueprint, clinical phase I) and H3B6527 (Eisai, clinical phaseI). Patents for selective inhibition of FGFR4 include WO2015059668,WO2015057938, and WO2015057963, etc. Currently, research on FGFR4inhibitors against tumors such as hepatocellular carcinoma isinsufficient, and it is still necessary to study and develop new FGFR4inhibitors.

SUMMARY OF THE INVENTION

One of the objects of the present invention is to disclose a new classof pyrimidine derivatives and pharmaceutically acceptable salts thereof.

The present invention provides a compound represented by formula (I) ora stereoisomer, tautomer thereof or a pharmaceutically acceptable saltthereof:

wherein:

each of R¹ is independently selected from alkyl, halogen, alkoxy,cycloalkyl, heterocyclyl, aryl, heteroaryl, —NR⁷R⁸, —C(O)NR⁷R⁸, —C(O)R⁹,—C(O)OR⁹ or —NR⁷C(O)R⁸, wherein the alkyl, alkoxy, cycloalkyl,heterocyclyl, aryl or heteroaryl is optionally further substituted byone or more substituents selected from the group consisting of hydroxyl,halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl,heteroaryl, —NR⁷R⁸, —C(O)NR⁷R⁸, —C(O)R⁹, —C(O)OR⁹ and —NR⁷C(O)R⁸;

R² is selected from the group:

—NR⁴C(O)CR⁵═CHR⁶ or —NR⁴C(O)C≡CR⁵;

R³ is a spiroheterocyclyl, wherein the spiroheterocyclyl is optionallyfurther substituted by one or more substituents selected from the groupconsisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy,cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkoxy, —NR⁷R⁸,—C(O)NR⁷R⁸, —C(O)R⁹, —C(O)OR⁹ and —NR⁷C(O)R⁸; or

R³ is a monocyclic heterocyclyl, wherein the monocyclic heterocyclyl isfurther substituted by one or more substituents selected from the groupconsisting of cycloalkyl and —NR⁷R⁸;

each of R⁴ is independently selected from hydrogen or alkyl, wherein thealkyl is optionally further substituted by one or more substituentsselected from the group consisting of hydroxy, halogen, nitro, cyano,alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkoxy,—NR⁷R⁸, —C(O)NR⁷R⁸, —C(O)R⁹, —C(O)OR⁹ and —NR⁷C(O)R⁸;

R⁵ and R⁶ are each independently selected from hydrogen, alkyl orhalogen, wherein the alkyl is optionally further substituted by one ormore substituents selected from the group consisting of hydroxy,halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl,heteroaryl, haloalkoxy, —NR⁷R⁸, —C(O)NR⁷R⁸, —C(O)R⁹, —C(O)OR⁹ and—NR⁷C(O)R⁸;

R⁷, R⁸ and R⁹ are each independently selected from hydrogen, alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally furthersubstituted by one or more substituents selected from the groupconsisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl,heterocyclyl, aryl, heteroaryl, —NR¹⁰R¹¹, C(O)NR¹⁰R¹¹, —C(O)R¹²,—C(O)OR¹² and —NR¹⁰C(O)R¹¹;

alternatively, R⁷ and R⁸ together with the N atom to which they areattached form a 4 to 8 membered heterocyclyl, wherein the 4 to 8membered heterocyclic ring contains one or more N, O, S(O)_(n) atoms,and the 4 to 8 membered heterocyclic ring is further substituted by oneor more substituents selected from the group consisting of hydroxy,halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl,heteroaryl, ═O, —NR¹⁰R¹¹, —C(O)NR¹⁰R¹¹, —C(O)R¹², —C(O)OR¹² and—NR¹⁰C(O)R¹¹;

R¹⁰, R¹¹ and R¹² are each independently selected from hydrogen, alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally furthersubstituted by one or more substituents selected from the groupconsisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl,heterocyclyl, aryl, heteroaryl, carboxylic acid and carboxylate;

m is 1, 2, 3 or 4; and

n is 0, 1, or 2.

A preferred embodiment of the present invention provides a compound offormula (I) or a stereoisomer, tautomer thereof or a pharmaceuticallyacceptable salt thereof, wherein R³ is a spiroheterocyclyl, wherein thespiroheterocyclyl is optionally further substituted by one or moresubstituents selected from the group consisting of hydroxy, halogen,nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl,haloalkoxy, —NR⁷R⁸, —C(O)NR⁷R⁸, —C(O)R⁹, —C(O)OR⁹ and —NR⁷C(O)R⁸, andR⁷, R⁸ and R⁹ are as defined in formula (I).

A preferred embodiment of the present invention provides a compound offormula (I) or a stereoisomer, tautomer thereof or a pharmaceuticallyacceptable salt thereof, which is a compound of formula (II) or astereoisomer, tautomer thereof or a pharmaceutically acceptable saltthereof:

wherein R¹ to R³ and m are as defined in formula (I).

A preferred embodiment of the present invention provides a compound offormula (I) or a stereoisomer, tautomer thereof or a pharmaceuticallyacceptable salt thereof, wherein R¹ is selected from halogen or alkoxy,preferably chlorine or methoxyl.

A preferred embodiment of the present invention provides a compound offormula (I) or a stereoisomer, tautomer thereof or a pharmaceuticallyacceptable salt thereof, wherein R² is —NHC(O)CH═CH₂.

A preferred embodiment of the present invention provides a compound offormula (I) or a stereoisomer, tautomer thereof or a pharmaceuticallyacceptable salt thereof, wherein R³ is a monospiroheterocyclyl,preferably a 3-membered/6-membered, 4-membered/4-membered,4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or5-membered/6-membered monospiroheterocyclyl, wherein themonospiroheterocyclyl is optionally further substituted by one or moresubstituents selected from the group consisting of alkyl, alkoxy,cycloalkyl, heterocyclyl, aryl and heteroaryl.

A preferred embodiment of the present invention provides a compound offormula (I) or a stereoisomer, tautomer thereof or a pharmaceuticallyacceptable salt thereof, wherein R² is —NHC(O)CH═CH₂, R³ is selectedfrom 3-membered/6-membered, 4-membered/4-membered,4-membered/5-membered, 4-membered/6-membered, 5-membered-/5-membered or5-membered/6-membered monospiroheterocyclyl, wherein themonospiroheterocyclyl is optionally further substituted by alkyl, thealkyl is preferably methyl or ethyl.

A preferred embodiment of the present invention provides a compound offormula (I) or a stereoisomer, tautomer thereof or a pharmaceuticallyacceptable salt thereof, wherein R² is —NHC(O)CH═CH₂, R³ is selectedfrom:

each R¹³ is independently selected from hydrogen, alkyl, alkoxy,cycloalkyl, heterocyclyl, aryl or heteroaryl, preferably hydrogen oralkyl, the alkyl is preferably ethyl.

A preferred embodiment of the present invention provides a compound offormula (I) or a stereoisomer, tautomer thereof or a pharmaceuticallyacceptable salt thereof, wherein R² is —NHC(O)CH═CH₂; R³ is selectedfrom 4-membered to 6-membered monocyclic heterocyclyl; preferablypiperidinyl or piperazinyl, wherein the piperidinyl or piperazinyl isfurther substituted by one or more substituents selected from the groupconsisting of cycloalkyl and —NR⁷R⁸, wherein R⁷ and R⁸ are as defined informula (I).

Further, a preferred embodiment of the present invention provides acompound of formula (I) or a stereoisomer, tautomer thereof or apharmaceutically acceptable salt thereof, wherein R² is —NHC(O)CH═CH₂;R³ is selected from 4-membered to 6-membered monocyclic heterocyclyl;preferably piperidinyl or piperazinyl, wherein the piperidinyl orpiperazinyl is further substituted by one or more substituents selectedfrom the group consisting of C₃-8 cycloalkyl and —NR⁷R⁸, wherein theC₃₋₈ cycloalkyl is preferably cyclopropyl, and each of R⁷ and R⁸ isindependently preferably hydrogen or alkyl, and the alkyl is preferablymethyl.

Typical compounds of the present invention include, but are not limitedto:

Ex- ample No. Structure Name 1

N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(2,7-diazaspiro[3.5]nonan-2-yl)phenyl)acrylamide 2

N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(4,7-diazaspiro[2.5]octan-7-yl)phenyl)acrylamide 3

N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(2,8-diazaspiro[4.5]decan-2-yl)phenyl)acrylamide 4

N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(7-ethyl-2,7-diazaspiro[3.5]nonan-2-yl)phenyl) acrylamide 5

N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(4-ethyl-4,7-diazaspiro[2.5]octan-7-yl)phenyl) acrylamide 6

N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(7-ethyl-2,7-diazaspiro[4.4]nonan-2-yl)phenyl) acrylamide 7

N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(4-(dimethylamino)piperidin-1-yl)phenyl)acrylamide 8

N-(5-(4-cyclopropylpiperazin-1-yl)-2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-)methylureido)pyrimidin-4-yl)amino)phenyl)acrylamide 9

N-(5-(4-(cyclopropyl)methyl)amino)piperidin-1-yl)-2-((6-(3-(2,6-dichloro-3,5-dimethoxy)phenyl)-1-methylureido)-4-yl)amino)phenyl)acrylamide

or stereoisomers, tautomers thereof or pharmaceutically acceptable saltsthereof.

Further, the present invention provides a preparation method for thecompound of formula (I), the method comprises:

reacting a compound of formula (Ie) with an acyl halide compound,preferably X—C(O)CR⁵═CHR⁶ or X—C(O)C≡CR⁵, and further removing the aminoprotecting group IV to obtain a compound of formula (If);

when R³ contains —NH₂ or —NH—, —NH₂ or —NH— may optionally be protectedby an N protecting group; the N protecting group is preferably —C(O)R⁹,more preferably tert-butoxycarbonyl;

further removing the amino protecting group R^(b) of the compound offormula (If) to obtain the compound of formula (I);

wherein:

R^(a) and R^(b) are each independently selected from N protectinggroups, preferably phenylsulfonyl, benzyloxycarbonyl, formyl,trifluoroacetyl or tert-butoxycarbonyl; more preferably phenylsulfonylor tert-butoxycarbonyl;

X is halogen;

R¹ to R⁶, R⁹ and m are as defined in formula (I).

Furthermore, the present invention provides a pharmaceutical compositioncomprising an effective amount of the compound of formula (I) or (II) orthe stereoisomer, tautomer thereof or the pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier, excipient or acombination thereof.

The present invention provides a method for inhibiting FGFR4, whichcomprises contacting the receptor with the compound of any one offormula (I) and (II) or the stereoisomer, tautomer thereof or thepharmaceutically acceptable salt thereof, or the pharmaceuticalcomposition thereof.

The present invention provides use of the compound of formula (I) or(II) or the stereoisomer, tautomer thereof or the pharmaceuticallyacceptable salt thereof, or the pharmaceutical composition thereof inpreparation of drugs of FGFR4 inhibitors.

The present invention provides use of the compound of formula (I) or(II) or the stereoisomer, tautomer thereof or the pharmaceuticallyacceptable salt thereof, or the pharmaceutical composition thereof inpreparation of drugs for treating diseases of FGFR4 over-expression.

The present invention provides use of the compound of formula (I) or(II) or the stereoisomer, tautomer thereof or the pharmaceuticallyacceptable salt thereof, or the pharmaceutical composition thereof inpreparation of drugs for treating diseases of FGF19 amplification.

The present invention provides use of the compound of formula (I) or(II) or the stereoisomer, tautomer thereof or a pharmaceuticallyacceptable salt thereof, or the pharmaceutical composition thereof inpreparation of drugs for treating cancer, wherein the cancer is selectedfrom the group consisting of non-small cell lung cancer, gastric cancer,multiple myeloma, hepatocellular carcinoma, cholangiocarcinoma,preferably hepatocellular carcinoma and cholangiocarcinoma.

The present invention provides a method for treating cancer, whichcomprises administering to a patient in need of treatment an effectiveamount of the compound of formula (I) or (II) or the stereoisomer,tautomer thereof or the pharmaceutically acceptable salt thereof, or thepharmaceutical composition thereof, wherein the cancer is selected fromthe group consisting of non-small cell lung cancer, gastric cancer,multiple myeloma, hepatocellular carcinoma, cholangiocarcinoma,preferably hepatocellular carcinoma and cholangiocarcinoma.

The present invention provides a method for treating diseases of FGFR4over-expression, which comprises administering to a patient in need oftreatment an effective amount of the compound of formula (I) or (II) orthe stereoisomer, tautomer thereof or the pharmaceutically acceptablesalt thereof, or the pharmaceutical composition thereof.

The present invention provides a method for treating diseases of FGF19amplification, which comprises administering to a patient in need oftreatment an effective amount of the compound of formula (I) or (II) orthe stereoisomer, tautomer thereof or the pharmaceutically acceptablesalt thereof, or the pharmaceutical composition thereof.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise stated, some of the terms used in the specification andclaims of the present invention are defined as follows:

“Alkyl” refers to an aliphatic hydrocarbon group comprising a C₁-C₂₀straight-chain or branched-chain when used as a group or part of agroup, preferably a C₁-C₁₀ alkyl, more preferably a C₁-C₆ alkyl.Examples of alkyl groups include, but are not limited to, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl,1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl,1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl,2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl and soon. The alkyl may be substituted or unsubstituted.

“Cycloalkyl” refers to a saturated or partially saturated monocyclic,fused, bridged, or spiro carbon ring, preferably a C₃-C₁₂ cycloalkyl,more preferably a C₃-C₈ cycloalkyl, and most preferably a C₃-C₆cycloalkyl. Examples of monocyclic cycloalkyl include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl,cycloheptatrienyl, cyclooctyl and so on, preferably cyclopropyl orcyclohexenyl.

“Spirocycloalkyl” refers to a 5 to 18 membered polycyclic groupcomprising two or more cyclic structures with single ring sharing onecommon carbon atom (named as spiro atom), which may contain one or moredouble bonds, but none of the rings have a completely conjugatedπ-electron aromatic system. Preferably 6 to 14 membered, more preferably7 to 10 membered. The spirocycloalkyl is classified into monospiro,dispiro, or multispiro cycloalkyl depending on the number of the spiroatoms shared between the rings, preferably monospiro or dispirocycloalkyl, preferably 4-membered/5-membered, 4-membered/6-membered,5-membered/5-membered, or 5-membered/6-membered. Non-limiting examplesof “spirocycloalkyl” include, but are not limited to spiro[4.5]decyl,spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.

“Fused cycloalkyl” refers to a 5 to 18 membered all-carbon polycyclicgroup, comprising two or more cyclic structures sharing an adjacent pairof carbon atoms with other rings, wherein one or more rings may containone or more double bonds, but none of the rings have a completelyconjugated π-electron aromatic system. Preferably 6 to 12 membered, morepreferably 7 to 10 membered. According to the number of ringsconstituted, it may be classified into a bicyclic, tricyclic,tetracyclic or polycyclic fused cycloalkyl, preferably a bicyclic ortricyclic ring, more preferably a 5-membered/5-membered or5-membered/6-membered bicycloalkyl. Non-limiting examples of “fusedcycloalkyl” include, but are not limited to, bicyclo[3.1.0]hexyl,bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decalinyl ortetradecahydrophenanthrenyl.

“Bridged cycloalkyl” refers to a 5 to 18 membered all-carbon polycyclicgroup, comprising two or more cyclic structures sharing two disconnectedcarbon atoms with each other, and one or more rings may contain one ormore double bonds, however, none of the rings have a completelyconjugated π-electron aromatic system. Preferably 6 to 12 membered, morepreferably 7 to 10 membered. It is preferably 6 to 14 membered, morepreferably 7 to 10 membered. According to the number of ringsconstituted, it may be classified into a bicyclic, tricyclic,tetracyclic or polycyclic bridged cycloalkyl, preferably a bicyclic, atricyclic or a tetracyclic ring, and more preferably a bicyclic or atricyclic ring. Non-limiting examples of “bridged cycloalkyl” include,but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl,bicyclo[3.2.1]octyl, (1s,5s)-dicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl,(1r,5r)-bicyclo[3.3.2]decyl.

Said cycloalkyl may be fused to an aryl, heteroaryl or heterocyclyl,wherein the ring attached to the parent structure is cycloalkyl,non-limiting examples include indanyl, tetrahydronaphthalenyl,benzocycloheptyl and the like. The cycloalkyl can be optionallysubstituted or unsubstituted.

“Heterocyclyl”, “heterocycle” or “heterocyclic” are used interchangeablyherein to refer to a non-aromatic heterocyclic group wherein one or moreof the ring-forming atoms are heteroatoms, such as oxygen, nitrogen,sulfur atoms, etc., including monocyclic, fused, bridged, and spirorings. It preferably has a 5- to 7-membered monocyclic ring or a 7- to10-membered bicyclic- or tricyclic ring which may contain 1, 2 or 3atoms selected from nitrogen, oxygen and/or sulfur. Examples of“heterocyclyl” include, but are not limited to morpholinyl,thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl,piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl,piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and piperazinyl. Theheterocyclyl may be substituted or unsubstituted.

“Spiroheterocyclyl” refers to a 5 to 18 membered polycyclic group withtwo or more cyclic structures and single rings share one common atomwith each other, wherein the said ring may contains one or more doublebonds, but none of the rings have a completely conjugated π-electronaromatic system, wherein one or more ring atoms are selected from theheteroatoms of nitrogen, oxygen or S(O)_(n) (wherein n is 0, 1 or 2) andthe remaining ring atoms are carbon. It is preferably 6- to 14-membered,more preferably 7- to 10-membered. The spiroheterocyclyl is classifiedinto a monospiroheterocyclyl, a dispiroheterocyclyl or apolyspiroheterocyclyl according to the number of shared spiro atomsbetween the rings, and is preferably a monospiroheterocyclyl or adispiroheterocyclyl. More preferably, it is 3-membered/6-membered,4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered,5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl.Wherein “a-membered/b-membered monospiroheterocyclyl” refers to aspiroheterocyclyl in which a-membered monocyclic ring and b-memberedmonocyclic ring share one atom with each other. Non-limiting examples of“spiroheterocyclyl” include, but are not limited to1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]decyl,7-oxaspiro[3.5]nonyl and 5-oxaspiro[2.4]heptyl.

“Fused heterocyclyl” refers to an all-carbon polycyclic group comprisingtwo or more cyclic structures that share an adjacent pair of atoms witheach other, and one or more rings may contain one or more double bonds,but none of the rings have completely conjugated π-electron aromaticsystem in which one or more ring atoms are selected from the heteroatomsof nitrogen, oxygen or S(O)_(n) (wherein n is 0, 1 or 2), and theremaining ring atoms are carbon. Preferably 6- to 14-membered, morepreferably 7- to 10-membered. Depending on the number of ringsconstituted, it may be classified into bicyclic, tricyclic, tetracyclicor polycyclic fused heterocyclyl, preferably a bicyclic or tricyclicring, more preferably a 5-membered/5-membered or 5-membered/6-memberedbicyclic fused heterocyclyl. Non-limiting examples of “fusedheterocyclyl” include, but are not limited tooctahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl,3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][1,4]dioxine.

“Bridged heterocyclyl” refers to a 5 to 18 membered polycyclic groupcomprising two or more cyclic structures sharing two disconnected atomswith each other, and one or more rings may contain one or more doublebonds, however, none of the rings have a completely conjugatedπ-electron aromatic system, in which one or more ring atoms are selectedfrom the heteroatoms of nitrogen, oxygen or S(O)_(n) (wherein n is 0, 1or 2), and the remaining ring atoms are carbon. It is preferably 6 to 14membered, more preferably 7 to 10 membered. Depending on the number ofrings constituted, it may be classified into a bicyclic, tricyclic,tetracyclic or polycyclic bridged heterocyclyl, preferably a bicyclic, atricyclic or a tetracyclic ring, and more preferably a bicyclic or atricyclic ring. Non-limiting examples of “fused heterocyclic groups”include, but are not limited to 2-azabicyclo[2.2.1]heptyl,2-azabicyclo[2.2.2]octyl and 2-azabicyclo[3.3.2]decyl. The heterocyclylring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein thering attached to the parent structure is heterocyclyl. The heterocyclylmay be optionally substituted or unsubstituted.

“Aryl” refers to a carbocyclic aromatic system containing one or tworings wherein the rings may be fused to each other. The term “aryl”includes aromatic groups such as phenyl, naphthyl, tetrahydronaphthyl.Preferably, the aryl is a C₆-C₁₀ aryl, more preferably the aryl is aphenyl and a naphthyl, and most preferably a phenyl. The aryl may besubstituted or unsubstituted. The “aryl” may be fused to heteroaryl,heterocyclyl or cycloalkyl, wherein the ring attached to the parentstructure is the aryl ring, non-limiting examples include, but are notlimited to:

“Heteroaryl” refers to an aromatic 5- to 6-membered monocyclic ring or9- to 10-membered bicyclic ring which may contain 1 to 4 atoms selectedfrom nitrogen, oxygen and/or sulfur. Examples of “heteroaryl” include,but are not limited to furyl, pyridyl, 2-oxo-1,2-dihydropyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl,oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl,thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl,benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolyl,indazolyl, benzoisothiazolyl, benzoxazolyl, and benzoisoxazolyl.Heteroaryl may be substituted or unsubstituted. The heteroaryl ring maybe fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ringattached to the parent structure is the heteroaryl ring, non-limitingexamples include, but are not limited to:

“Alkoxy” refers to a group of alkyl-O—. Wherein the alkyl group is asdefined herein. The alkoxy of C₁-C₆ is preferred. Examples thereofinclude, but are not limited to methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, tert-butoxy and the like.

“Hydroxy” refers to an —OH group.

“Halogen” refers to fluorine, chlorine, bromine and iodine, preferablychlorine, bromine and iodine.

“Amino” refers to —NH₂.

“Cyano” refers to —CN.

“Nitro” refers to —NO₂.

“Benzyl” refers to —CH₂-phenyl.

“Carboxy” refers to —C(O)OH.

“carboxylatyl” refers to —C(O)O(alkyl) or (cycloalkyl), wherein alkyl,cycloalkyl are as defined above.

“Boc” refers to tert-butoxycarbonyl.

“N protecting group” refers to a molecule containing two or morefunctional groups. In order to protect —NH₂ or —NH— from reaction inorganic synthesis, a certain reagent is usually used, and the protectinggroup is removed after the reaction is completed. N protecting groupsinclude, but are not limited to tert-butoxycarbonyl, benzyloxycarbonyl,formyl or trifluoroacetyl.

“Substituted” refers to one or more hydrogen in the group, preferably upto 5, more preferably 1 to 3 hydrogen, independently of each other,substituted by a corresponding number of substituents. It goes withoutsaying that the substituents are only in their possible chemicalpositions, and those skilled in the art will be able to determine (byexperiment or theory) substitution that may or may not be possiblewithout undue effort. For example, the combination of an amino orhydroxyl group having free hydrogen(s) with a carbon atom having anunsaturated (e.g., olefinic) bond may be unstable.

As used herein, “substitute” or “substituted”, unless otherwiseindicated, refers to that the group may be substituted by one or moregroups selected from the group consisting of alkyl, alkenyl, alkynyl,alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxy, nitro,cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy,heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino,haloalkyl, hydroxyalkyl, carboxyl, carboxylic ester group, ═O, —NR⁷R⁸,—C(O)NR⁷R⁸, —C(O)R⁹, —C(O)OR⁹ or —NR⁷C(O)R⁸.

R⁷, R⁸ and R⁹ are each independently selected from hydrogen, alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally furthersubstituted by one or more substituents selected from the groupconsisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy,cycloalkyl, heterocyclyl, aryl, heteroaryl, —NR¹⁰R¹¹, —C(O)NR¹⁰R¹¹,—C(O)R¹², —C(O)OR¹² or —NR¹⁰C(O)R¹¹;

Alternatively, R⁷ and R⁸ together with the N atom to which they areattached form a 4 to 8 membered heterocyclyl, wherein the 4 to 8membered heterocyclic ring contains one or more N, O, S(O)_(n) atoms,and the 4 to 8 membered heterocyclic ring is further substituted by oneor more substituents selected from the group consisting of hydroxy,halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl,heteroaryl, ═O, —NR¹⁰R¹¹, —C(O)NR¹⁰R¹¹, —C(O)R¹², —C(O)OR¹² and—NR¹⁰C(O)R¹¹;

R¹⁰, R¹¹ and R¹² are each independently selected from hydrogen, alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally furthersubstituted by one or more substituents selected from the groupconsisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl,heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylate.

“Pharmaceutically acceptable salt” refers to certain salts of the abovecompounds which retain their original biological activity and aresuitable for pharmaceutical use. The pharmaceutically acceptable salt ofthe compound represented by formula (I) may be a metal salt, an aminesalt formed with a suitable acid, the metal salt is preferably an alkalimetal or an alkaline earth metal salt, and a suitable acid including aninorganic acid and an organic acid, such as acetic acid, benzenesulfonicacid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonicacid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid,hydrochloric acid, isethionic acid, lactic acid, malic acid, maleicacid, mandelic acid, methanesulfonic acid, nitric acid, phosphoric acid,succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, andthe like. Particularly preferred are hydrochloric acid, hydrobromicacid, phosphoric acid and sulfuric acid, and most preferred is thehydrochloride salt.

“Pharmaceutical composition” refers to a mixture comprising one or moreof the compounds described herein or a physiologically pharmaceuticallyacceptable salt or a prodrug thereof and other chemical components, aswell as other components such as physiologically pharmaceuticallyacceptable carriers and excipients. The purpose of the pharmaceuticalcomposition is to promote the administration to the organism, whichfacilitates the absorption of the active ingredient and thereby exertsbiological activity.

Method for Synthesizing the Compound of the Present Invention

In order to accomplish the object of the present invention, thefollowing technical solutions are adopted:

The preparation method of the compound of formula (I) or a salt thereofof the present invention comprises the following steps:

The compound of formula (Ia) and the compound of formula (Ib) aresubjected to a Buchwald reaction, preferably in the presence of4,5-bisdiphenylphosphino-9,9-dimethylxanthene, palladium catalyzedtris(dibenzalacetone)dipalladium and cesium carbonate, to obtain acompound of formula (Ic); the amino of the compound of formula (Ic) isprotected, preferably with di-tert-butyl dicarbonate, to obtain anR^(b)-protected compound of formula (Id); the nitro of the compound offormula (Id) is reduced under hydrogen, optionally further alkylated toobtain a compound of formula (Ie); reacting the compound of formula (Ie)with an acyl halide compound, preferably X—C(O)CR⁵═CHR⁶ or X—C(O)C≡CR⁵,and the amino protecting group IV is further removed to obtain acompound of formula (If); and the amino protecting group R^(b) of thecompound of formula (If) is further removed to obtain a compound offormula (I);

wherein:

R^(a) and R^(b) are each independently selected from N protectinggroups, preferably phenylsulfonyl, benzyloxycarbonyl, formyl,trifluoroacetyl and tert-butoxycarbonyl; more preferably phenylsulfonyland tert-butoxycarbonyl;

X is halogen;

in the reaction scheme, when R³ contains —NH₂ or —NH—, —NH₂ or —NH— mayoptionally be protected by an N protecting group; the N protecting groupis preferably —C(O)R⁹, more preferably a tert-butoxycarbonyl group;

R¹ to R⁶, R⁹ and m are as defined in formula (I).

DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing changes in mean tumor volume of xenografts ofhepatocellular carcinoma tumor cell Huh7 tumor-bearing BALB/c nude miceby the compound of Example 108 of WO2015057938 and the compound ofExample 5 of the present invention in Test Example 3.

FIG. 2 is a graph showing changes in mean relative tumor volume ofxenografts of hepatocellular carcinoma tumor cell Huh7 tumor-bearingBALB/c nude mice by the compound of Example 108 of WO2015057938 and thecompound of Example 5 of the present invention in Test Example 3.

FIG. 3 is a graph showing changes in body weight of hepatocellularcarcinoma tumor cell Huh7 tumor-bearing BALB/c nude mice by the compoundof Example 108 of WO2015057938 and the compound of Example 5 of thepresent invention in Test Example 3.

EMBODIMENT

The present invention is further described in the following examples,but these examples are not intended to limit the scope of the presentinvention.

EXAMPLE

The preparation of representative compounds of formula (I) and relateddata about structural identification are provided by the examples. It isto be understood that the following examples are intended to illustrateand not to limit the present invention. The ¹H NMR spectrum wasdetermined using a Bruker instrument (400 MHz) and the chemical shift isexpressed in ppm. The internal standard of tetramethylsilane (0.00 ppm)was used. ¹H NMR representation: s=singlet, d=doublet, t=triplet,m=multiplet, br=broadened, dd=doublet of doublet, dt=doublet of triplet.If a coupling constant is provided, its unit is Hz.

Mass spectrometry was measured by LC/MS tester, and the ionizationmethod was ESI or APCI.

Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate is used as thesilica gel plate of thin layer chromatography. The dimension of thesilica gel plate used in thin layer chromatography (TLC) are 0.15 mm to0.2 mm, and the dimension of the silica gel plate used for theseparation and purification of products by thin layer chromatography are0.4 mm to 0.5 mm.

Column chromatography generally uses Yantai Huanghai silica gel of200300 mesh as carrier.

In the following examples, all temperatures are in degrees Celsiusunless otherwise indicated, and the various starting materials andreagents are either commercially available or synthesized according toknown methods unless otherwise indicated, and the commercially availablematerials and reagents are used directly without further purification.Unless otherwise indicated, commercially available manufacturers,including but not limited to Aldrich Chemical Company, ABCR GmbH & Co.KG, Acros Organics, Guangzan Chemical Technology Co., Ltd. and JingyanChemical Technology Co., Ltd., etc.

CD₃OD: deuterated methanol.

CDCl₃: deuterated chloroform.

DMSO-d₆: deuterated dimethyl sulfoxide.

The argon atmosphere refers to that the reaction flask is equipped withan argon balloon having a volume of about 1 L.

Unless otherwise stated, the solution in the reaction used in examplesrefers to an aqueous solution.

The compounds are purified using a silica gel column chromatographyeluent system and thin layer chromatography, wherein the eluent systemis selected from: A: petroleum ether and ethyl acetate system; B:dichloromethane and methanol system; The volume ratio of solvents variesdepending on the polarity of the compounds, and a small amount of anacidic or alkaline reagents such as acetic acid or triethylamine mayalso be added.

Example 1N-(2-((6-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(2,7-diazaspiro[3.5]nonan-2-yl)phenyl)acrylamide

Step 1 Tert-butylN-(4-bromo-2-nitro-phenyl)-N-tert-butoxycarbonyl-carbamate

4-Bromo-2-nitroaniline 1a (7.50 g, 34.56 mmol) was dissolved in 90 mL oftetrahydrofuran, the solution was added with di-tert-butyl dicarbonate(15.08 g, 69.12 mmol) and 4-dimethylaminopyridine (200 mg, 1.64 mmol),heated to 80° C. and reacted for 2 hours. The reaction solution wasconcentrated under reduced pressure, the resulting residue was purifiedby silica gel column chromatography (eluent: A system) to obtaintert-butyl N-(4-bromo-2-nitro-phenyl)-N-tert-butoxycarbonyl-carbamate 1b(12.6 g, yellow solid), yield: 87.4%.

MS m/z (ESI): 361.0 [M+1-56]

Step 2 Tert-butyl (4-bromo-2-nitrophenyl)carbamate

Tert-butyl N-(4-bromo-2-nitro-phenyl)-N-tert-butoxycarbonyl-carbamate 1b(7.12 g, 17.1 mmol) and potassium carbonate (7.08 g, 51.2 mmol) weredissolved in 140 mL of acetonitrile, the solution was heated to 35° C.and reacted for 1.5 hours. The reaction solution was filtered, thefiltrate was concentrated under reduced pressure, the resulting residuewas purified by silica gel column chromatography (eluent: A system) toobtain tert-butyl (4-bromo-2-nitrophenyl)carbamate 1c (4.49 g, brightyellow solid), yield: 82.8%.

MS m/z (ESI): 216.8 [M+1-100]

Step 33-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-(6-chloropyrimidin-4-yl)-1-methylurea

6-Chloro-N-methylpyrimidin-4-amine 1e (300 mg, 2.09 mmol) was dissolvedin 10 mL of N,N-dimethylformamide, the solution was cooled to 0° C.,added with 60% sodium hydride (167 mg, 4.18 mmol), and stirred at roomtemperature for 30 minutes.2,4-dichloro-3-isocyanato-1,5-dimethoxy-4-methyl benzene 1d (674 mg,2.72 mmol) was dissolved in 5 mL of N,N-dimethylformamide and addeddropwise to the reaction solution, and reacted at room temperature for0.5 hour. The reaction solution was added with 50 mL of water, and awhite solid was precipitated. After filtration, the filter cake wasrecrystallized with ethyl acetate to obtain3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(6-chloropyrimidin-4-yl)-1-methylurea1f (710 mg, white solid), yield: 86.8%.

MS m/z (ESI): 392.8 [M+1]

Step 4 Tert-butyl(6-chloropyrimidin-4-yl)(methyl)carbamoyl-(2,6-dichloro-3,5-dimethoxyphenyl)carbamate

3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-(6-chloropyrimidin-4-yl)-1-methylurea1f (1.20 g, 3.06 mmol) was dissolved in 20 mL of tetrahydrofuran, thesolution was cooled to 0° C., added with di-tert-butyl dicarbonate (1.34g, 6.13 mmol) and 4-dimethylaminopyridine (187 mg, 1.53 mmol), heated to75° C. and refluxed for 1 hour. The reaction solution was concentratedunder reduced pressure, and added with 30 mL of dichloromethane, washedwith water (20 mL×2) and saturated sodium chloride solution (20 mL)successively, dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure, the resulting residue was purifiedby silica gel column chromatography (eluent: A system) to obtaintert-butyl(6-chloropyrimidin-4-yl)(methyl)carbamoyl-(2,6-dichloro-3,5-dimethoxyphenyl)carbamate1g (1.34 g, white solid), yield: 88.9%.

MS m/z (ESI): 492.8 [M+1]

Step 5 Tert-butyl2-(4-((tert-butoxycarbonyl)amino)-3-nitrophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

Tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate 1h (440 mg, 1.94mmol), tert-butyl (4-bromo-2-nitrophenyl)carbamate 1c (616 mg, 1.94mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (229 mg, 0.388mmol), tris(dibenzylideneacetone)dipalladium (352 mg, 0.388 mmol) andcesium carbonate (1.90 g, 5.83 mmol) were dissolved in 15 mL ofmethylbenzene, the reaction mixture was reacted at 115° C. for 4 hoursunder argon atmosphere. The reaction solution was cooled to roomtemperature, filtered, and concentrated under reduced pressure, theresulting residue was purified by silica gel column chromatography(eluent: A system) to obtain tert-butyl2-(4-((tert-butoxycarbonyl)amino)-3-nitrophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate1i (600 mg, red solid), yield: 66.7%.

MS m/z (ESI): 485.0 [M+23]

Step 6 Tert-butyl2-(4-amino-3-nitrophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

Tert-butyl2-(4-((tert-butoxycarbonyl)amino)-3-nitrophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate1i (600 mg, 1.30 mmol) and potassium hydroxide (218 mg, 3.89 mmol) weredissolved in 10 mL of a mixed solution of water and ethanol (V/V=1/4),the solution was heated to reflux for 3 hours. The reaction solution wasconcentrated under reduced pressure, 20 mL of ethyl acetate was added,layered, the aqueous phase was extracted with ethyl acetate (20 mL×2),the organic phases were combined and washed with water (20 mL×2), driedover anhydrous sodium sulfate, filtered, and concentrated under reducedpressure, the resulting residue was purified by silica gel columnchromatography (eluent: A system) to obtain tert-butyl2-(4-amino-3-nitrophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate 1j(400 mg, red solid), yield: 85.1%.

MS m/z (ESI): 362.1 [M+1]

Step 7 Tert-butyl2-(4-((6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-3-nitrophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

Tert-butyl(6-chloropyrimidin-4-yl)(methyl)carbamoyl-(2,6-dichloro-3,5-dimethoxyphenyl)carbamate1g (450 mg, 0.909 mmol),2-(4-amino-3-nitrophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate 1j(300 mg, 0.828 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene(96 mg, 0.165 mmol), tris(dibenzylideneacetone)dipalladium (75 mg, 0.082mmol) and cesium carbonate (810 mg, 2.40 mmol) were dissolved in 15 mLof toluene, the reaction mixture was reacted at 110° C. for 4 hours. Thereaction solution was cooled to room temperature, filtered, andconcentrated under reduced pressure, the resulting residue was purifiedby silica gel column chromatography (eluent: A system) to obtaintert-butyl2-(4-((6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-3-nitrophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate1k (427 mg, red solid), yield: 63.3%.

¹H NMR (400 MHz, CDCl₃) δ 9.15 (s, 1H), 8.59 (s, 1H), 8.18 (d, J=8.4 Hz,1H), 7.42 (s, 1H), 7.11 (d, J=6.4 Hz, 1H), 6.75-6.71 (m, 1H), 6.59 (s,1H), 3.93 (s, 6H), 3.70 (s, 4H), 3.63 (s, 2H), 3.46-3.36 (m, 4H),1.82-1.76 (m, 4H), 1.49 (s, 9H), 1.41 (s, 9H).

Step 8 Tert-butyl2-(4-((tert-butoxycarbonyl)(6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-)methylurea)pyrimidin-4-yl)amino)-3-nitrophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

Tert-butyl2-(4-((6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-3-nitrophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate1k (500 mg, 0.611 mmol) was dissolved in 10 mL of tetrahydrofuran, thesolution was cooled to 0° C., added with di-tert-butyl dicarbonate (200mg, 0.917 mmol) and 4-dimethylaminopyridine (37.3 mg, 0.306 mmol), andheated to reflux for 3 hours. The reaction solution was concentratedunder reduced pressure and the resulting residue was purified by silicagel column chromatography (eluent: A system) to obtain tert-butyl2-(4-((tert-butoxycarbonyl)(6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-)methylurea)pyrimidin-4-yl)amino)-3-nitrophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate1l (500 mg, yellow solid), yield: 89.1%.

Step 9 Tert-butyl2-(3-amino-4-((tert-butoxycarbonyl)(6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)phenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

Tert-butyl2-(4-((tert-butoxycarbonyl)(6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-)methylurea)pyrimidin-4-yl)amino)-3-nitrophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate1l (500 mg, 0.545 mmol) was dissolved in 10 mL of methanol, the solutionwas added with Raney nickel (200 mg) was added and reacted under theprotection of hydrogen for 12 hours at room temperature. The reactionsolution was concentrated under reduced pressure and the resultingresidue was purified by silica gel column chromatography (eluent: Asystem) to obtain tert-butyl2-(3-amino-4-((tert-butoxycarbonyl)(6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)phenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate1m (300 mg, red solid), yield: 62.0%.

¹H NMR (400 MHz, CDCl₃) δ 8.66 (s, 1H), 8.21 (s, 1H), 6.81 (d, J=8.4 Hz,1H), 6.59 (s, 1H), 5.9-5.85 (m, 1H), 5.84-5.79 (m, 1H), 3.94 (s, 6H),3.63 (s, 3H), 3.6 (s, 4H), 3.43-3.32 (m, 4H), 1.82-1.72 (m, 4H), 1.46(s, 9H), 1.42 (s, 9H), 1.41 (s, 9H).

Step 10 Tert-butyl2-(3-acrylamido-4-((tert-butoxycarbonyl)(6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)phenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

Tert-butyl2-(3-amino-4-((tert-butoxycarbonyl)(6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)phenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate1m (200 mg, 0.225 mmol) was dissolved in 10 mL of dichloromethane, thesolution was added with N,N-diisopropylethylamine (87 mg, 0.676 mmol)and acryloyl chloride (22 mg, 0.248 mmol) under an ice bath, and reactedat room temperature for 0.5 hours. The reaction solution wasconcentrated under reduced pressure and the resulting residue waspurified by silica gel column chromatography (eluent: A system) toobtain tert-butyl2-(3-acrylamido-4-((tert-butoxycarbonyl)(6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)phenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylatein (200 mg, pale yellow solid), yield: 94.3%.

Step 11N-(2-((6-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(2,7-diazaspiro[3.5]nonan-2-yl)phenyl)acrylamide

Tert-butyl2-(3-acrylamido-4-((tert-butoxycarbonyl)(6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)phenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylatein (200 mg, 0.84 mmol) was dissolved in 10 mL of dichloromethane, thesolution was added with 5 mL of trifluoroacetic acid under an ice bath,reacted at room temperature for 12 hours under the protection ofnitrogen. The reaction solution was concentrated under reduced pressure,20 mL of mixed solution of dichloromethane and methanol (V/V=10/1) wasadded, washed with saturated sodium bicarbonate solution (10 mL), andthe organic phase was dried over anhydrous sodium sulfate, filtered,concentrated under reduced pressure, and the resulting residue waspurified by silica gel thin layer chromatography (eluent: B system) toobtainN-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(2,7-diazaspiro[3.5]nonan-2-yl)phenyl)acrylamide1 (80 mg, pale yellow solid), yield: 58.8%.

MS m/z (ESI): 640.8 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 12.1 (s, 1H), 9.64 (s, 1H), 8.82 (s, 1H),8.3 (s, 1H), 7.22 (d, J=8.4 Hz, 1H), 6.95-6.86 (m, 2H), 6.58-6.48 (m,1H), 6.28 (d, J=8.0 Hz, 1H), 6.22 (d, J=8.8 Hz, 1H), 5.76 (s, 1H), 5.71(d, J=10.4 Hz, 1H), 3.93 (s, 6H), 3.63 (s, 4H), 3.21 (s, 3H), 3.12-3.01(m, 4H), 2.0-1.91 (m, 4H).

Example 2N-(2-((6-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(4,7-diazaspiro[2.5]octan-7-yl)phenyl)acrylamide

Step 1 Tert-butyl7-(4-((tert-butoxycarbonyl)amino)-3-nitrophenyl)-4,7-diazaspiro[2.5]octane-4-carboxylate

Tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate 2a (803 mg, 3.78mmol), tert-butyl (4-bromo-2-nitrophenyl)carbamate 1c (1.02 g, 3.15mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (35 mg, 0.063mmol), tris(dibenzylideneacetone)dipalladium (115 mg, 0.126 mmol) andcesium carbonate (3.08 g, 9.46 mmol) were dissolved in 30 mL of tolueneand reacted at 110° C. for 6 hours under the protection of argon. Thereaction solution was cooled to room temperature, filtered, andconcentrated under reduced pressure and the resulting residue waspurified by silica gel column chromatography (eluent: A system) toobtain tert-butyl7-(4-((tert-butoxycarbonyl)amino)-3-nitrophenyl)-4,7-diazaspiro[2.5]octane-4-carboxylate2b (240 mg, red solid), yield: 17.0%.

MS m/z (ESI): 348 [M-100]

Step 2 Tert-butyl7-(4-amino-3-nitrophenyl)-4,7-diazaspiro[2.5]octane-4-carboxylate

Tert-butyl7-(4-((tert-butoxycarbonyl)amino)-3-nitrophenyl)-4,7-diazaspiro[2.5]octane-4-carboxylate2b (240 mg, 0.53 mmol) and potassium hydroxide (90 mg, 1.61 mmol) weredissolved in 8 mL of a mixed solution of water and ethanol (V/V=1/3),and heated to reflux for 6 hours. The reaction solution was concentratedunder reduced pressure, 20 mL of ethyl acetate and 10 mL of water wereadded, seperated, the aqueous phase was extracted with ethyl acetate (10mL×2), the organic phases were combined and washed with water (20 mL×2),dried over anhydrous sodium sulfate, filtered, and concentrated underreduced pressure to obtain crude product of tert-butyl7-(4-amino-3-nitrophenyl)-4,7-diazaspiro[2.5]octane-4-carboxylate 2c(160 mg, red solid), yield: 86.6%.

¹H NMR (400 MHz, CDCl₃) δ 7.5 (s, 1H), 7.19-7.15 (m, 1H), 6.76 (d, J=8.4Hz, 1H), 5.95-5.75 (m, 2H), 3.75-3.65 (m, 2H), 3.10-3.02 (m, 2H),2.95-2.80 (m, 2H), 1.47 (s, 9H), 1.10-1.04 (m, 2H), 0.89-0.84 (m, 2H).

Step 3 Tert-butyl7-(4-((6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-3-nitrophenyl)-4,7-diazaspiro[2.5]octane-4-carboxylate

Tert-butyl(6-chloropyrimidin-4-yl)(methyl)carbamoyl-(2,6-dichloro-3,5-dimethoxyphenyl)carbamate1g (248 mg, 0.51 mmol), tert-butyl7-(4-amino-3-nitrophenyl)-4,7-diazaspiro[2.5]octane-4-carboxylate 2c(160 mg, 0.46 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (53mg, 0.092 mmol), tris(dibenzylideneacetone)dipalladium (42 mg, 0.046mmol) and cesium carbonate (449 mg, 1.38 mmol) were dissolved in 10 mLof toluene and reacted at 110° C. for 4 hours. The reaction solution wascooled to room temperature, filtered, and concentrated under reducedpressure, the resulting residue was purified by silica gel columnchromatography (eluent: A system) to obtain tert-butyl7-(4-((6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-3-nitrophenyl)-4,7-diazaspiro[2.5]octane-4-carboxylate2d (262 mg, red solid), yield: 71.0%.

MS m/z (ESI): 803.8 [M+1]

Step 4 Tert-butyl7-(4-((tert-butoxycarbonyl)(6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-3-nitrophenyl)-2,7-diazaspiro[2.5]octane-4-carboxylate

Tert-butyl7-(4-((6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-3-nitrophenyl)-4,7-diazaspiro[2.5]octane-4-carboxylate2d (262 mg, 0.326 mmol) was dissolved in 10 mL of tetrahydrofuran, thesolution was cooled to 0° C., added with di-tert-butyl dicarbonate (107mg, 0.489 mmol) and 4-dimethylaminopyridine (20 mg, 0.163 mmol) wereadded, and t heated to reflux for 1 hour. The reaction solution wasconcentrated under reduced pressure and the resulting residue waspurified by silica gel column chromatography (eluent: A system) toobtain tert-butyl7-(4-((tert-butoxycarbonyl)(6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-3-nitrophenyl)-2,7-diazaspiro[2.5]octane-4-carboxylate2e (260 mg, yellow solid), yield: 88.4%.

¹H NMR (400 MHz, CDCl₃) δ 8.55 (s, 1H), 8.44 (s, 1H), 7.62 (s, 1H),7.22-7.05 (m, 2H), 6.59 (s, 1H), 3.94 (s, 6H), 3.78 (t, J=4.4 Hz, 2H),3.66 (s, 3H), 3.33 (t, J=4.4 Hz, 2H), 3.12 (s, 2H), 1.48 (s, 9H),1.44-1.38 (m, 18H), 1.14-1.09 (m, 2H), 0.96-0.89 (m, 2H).

Step 5 Tert-butyl7-(3-amino-4-((tert-butoxycarbonyl)(6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)phenyl)-4,7-diazaspiro[2.5]octane-4-carboxylate

Tert-butyl7-(4-((tert-butoxycarbonyl)(6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-3-nitrophenyl)-2,7-diazaspiro[2.5]octane-4-carboxylate2e (260 mg, 0.288 mmol) was dissolved in 9 mL of a mixed solution oftetrahydrofuran and methanol (V/V=1/2), and Raney nickel (100 mg) wasadded, reacted for 6 hours at room temperature under the protection ofhydrogen. The reaction solution was filtered, concentrated under reducedpressure and the resulting residue was purified by silica gel columnchromatography (eluent: A system) to obtain tert-butyl7-(3-amino-4-((tert-butoxycarbonyl)(6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)phenyl)-4,7-diazaspiro[2.5]octane-4-carboxylate2f (200 mg, yellow solid), yield: 79.7%.

Step 6 Tert-butyl7-(3-acrylamido-4-((tert-butoxycarbonyl)(6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)phenyl)-4,7-diazaspiro[2.5]octane-4-carboxylate

Tert-butyl7-(3-amino-4-((tert-butoxycarbonyl)(6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)phenyl)-4,7-diazaspiro[2.5]octane-4-carboxylate2f (200 mg, 0.229 mmol) was dissolved in 10 mL of dichloromethane, thesolution was added with N,N-diisopropylethylamine (89 mg, 0.687 mmol)and acryloyl chloride (23 mg, 0.252 mmol) under an ice bath, and reactedfor 0.5 hour at room temperature. The reaction solution was concentratedunder reduced pressure and the resulting residue was purified by silicagel column chromatography (eluent: A system) to obtain tert-butyl7-(3-acrylamido-4-((tert-butoxycarbonyl)(6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)phenyl)-4,7-diazaspiro[2.5]octane-4-carboxylate2g (180 mg, yellow solid), yield: 84.8%.

¹H NMR (400 MHz, CDCl₃) δ 8.64 (s, 1H), 8.28 (s, 1H), 8.11-8.0 (m, 1H),7.07-7.02 (m, 1H), 6.59 (s, 1H), 6.37 (d, J=16.8 Hz, 1H), 6.25-6.15 (m,1H), 5.75 (d, J=10.4 Hz, 1H), 3.95 (s, 6H), 3.85-3.77 (m, 2H), 3.64 (s,3H), 3.35-3.25 (m, 2H), 3.12 (s, 2H), 1.48 (s, 9H), 1.42 (s, 9H), 1.34(s, 9H), 1.14-1.06 (m, 2H), 0.97-0.91 (m, 2H).

Step 7N-(2-((6-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(4,7-diazaspiro[2.5]octan-7-yl)phenyl)acrylamide

Tert-butyl7-(3-acrylamido-4-((tert-butoxycarbonyl)(6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)phenyl)-4,7-diazaspiro[2.5]octane-4-carboxylate2g (170 mg, 0.183 mmol) was dissolved in 6 mL of dichloromethane, thesolution was added with 3 mL of trifluoroacetic acid under an ice bath,and reacted at room temperature for 12 hours under the protection ofnitrogen. The reaction solution was concentrated under reduced pressure,20 mL of a mixed solution of dichloromethane and methanol (V/V=10/1) wasadded, washed with saturated sodium bicarbonate solution (10 mL), andthe organic phase was concentrated under reduced pressure, and theresulting residue was purified by silica gel thin layer chromatography(eluent: B system) to obtainN-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(4,7-diazaspiro[2.5]octan-7-yl)phenyl)acrylamide2 (40 mg, pale yellow solid), yield: 34.8%. MS m/z (ESI): 626.9 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 12.09 (s, 1H), 9.84 (s, 1H), 9.01 (s, 1H),8.32 (s, 1H), 7.46-7.31 (m, 2H), 6.89 (s, 1H), 6.85 (d, J=8.8 Hz, 1H),6.63-6.48 (m, 1H), 6.39-6.13 (m, 2H), 5.73 (d, J=9.6 Hz, 1H), 3.93 (s,6H), 3.29-3.11 (m, 9H), 1.13-0.99 (m, 2H), 0.97-0.78 (m, 2H).

Example 3N-(2-((6-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(2,8-diazaspiro[4.5]decan-2-yl)phenyl)acrylamide

Step 1 Tert-butyl2-(4-((tert-butoxycarbonyl)amino)-3-nitrophenyl)-2,8-diazaspiro[2.5]decane-8-carboxylate

Tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate 3a (500 mg, 2.08mmol), tert-butyl (4-bromo-2-nitrophenyl)carbamate 1c (660 mg, 2.08mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (230 mg, 0.42mmol), tris(dibenzylideneacetone)dipalladium (380 mg, 0.42 mmol) andcesium carbonate (2.03 g, 6.24 mmol) were dissolved in 20 mL of tolueneand reacted at 120° C. for 4 hours. The reaction solution was cooled toroom temperature, filtered, and concentrated under reduced pressure, theresulting residue was purified by silica gel column chromatography(eluent: A system) to obtain tert-butyl2-(4-((tert-butoxycarbonyl)amino)-3-nitrophenyl)-2,8-diazaspiro[2.5]decane-8-carboxylate3b (260 mg, red solid), yield: 26.2%. MS m/z (ESI): 477.0 [M+1]

Step 2 Tert-butyl2-(4-amino-3-nitrophenyl)-2,8-diazaspiro[4.5]decane-8-carboxylate

Tert-butyl2-(4-((tert-butoxycarbonyl)amino)-3-nitrophenyl)-2,8-diazaspiro[2.5]decane-8-carboxylate3b (260 mg, 0.54 mmol) and potassium hydroxide (91.83 mg, 1.64 mmol)were dissolved in 8 mL of a mixed solution of water and ethanol(V/V=1/3), heated to 90° C. and reacted for 6 hours. The reactionsolution was concentrated under reduced pressure, 10 mL of ethyl acetatewas added, layered, the aqueous phase was extracted with ethyl acetate(10 mL×2), the organic phases were combined and dried over anhydroussodium sulfate, filtered, and concentrated under reduced pressure toobtain crude product of tert-butyl2-(4-amino-3-nitrophenyl)-2,8-diazaspiro[4.5]decane-8-carboxylate 3c(160 mg, black red solid), yield: 75.5%.

MS m/z (ESI): 377.0 [M+1]

Step 3 Tert-butyl2-(4-((6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-3-nitrophenyl)-2,8-diazaspiro[4.5]decane-8-carboxylate

Tert-butyl(6-chloropyrimidin-4-yl)(methyl)carbamoyl-(2,6-dichloro-3,5-dimethoxyphenyl)carbamate1g (216 mg, 0.44 mmol), tert-butyl2-(4-amino-3-nitrophenyl)-2,8-diazaspiro[4.5]decane-8-carboxylate 3c(150 mg, 0.40 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (46mg, 0.08 mmol), tris(dibenzylideneacetone)dipalladium (146 mg, 0.04mmol) and cesium carbonate (390 mg, 1.20 mmol) were dissolved in 10 mLof toluene and reacted at 110° C. for 4 hours. The reaction solution wascooled to room temperature, filtered, and concentrated under reducedpressure, the resulting residue was purified by silica gel columnchromatography (eluent: A system) to obtain tert-butyl2-(4-((6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-3-nitrophenyl)-2,8-diazaspiro[4.5]decane-8-carboxylate3d (80 mg, red solid), yield: 27.1%.

Step 4 Tert-butyl2-(4-((tert-butoxycarbonyl)(6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-3-nitrophenyl)-2,8-diazaspiro[4.5]decane-8-carboxylate

Tert-butyl2-(4-((6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-3-nitrophenyl)-2,8-diazaspiro[4.5]decane-8-carboxylate3d (80 mg, 0.096 mmol) was dissolved in 10 mL of tetrahydrofuran,di-tert-butyl dicarbonate (32 mg, 0.144 mmol) and4-dimethylaminopyridine (6 mg, 0.046 mmol) were added, heated to 78° C.and reacted for 1 hour. The reaction solution was concentrated underreduced pressure to obtain crude product of tert-butyl2-(4-((tert-butoxycarbonyl)(6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-3-nitrophenyl)-2,8-diazaspiro[4.5]decane-8-carboxylate3e (89 mg, yellow solid), yield: 100%.

Step 5 Tert-butyl2-(3-amino-4-((tert-butoxycarbonyl)(6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)phenyl)-2,8-diazaspiro[4.5]decane-8-carboxylate

Tert-butyl2-(4-((tert-butoxycarbonyl)(6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-3-nitrophenyl)-2,8-diazaspiro[4.5]decane-8-carboxylate3e (89 mg, 0.0955 mmol) was dissolved in 6 mL of a mixed solution oftetrahydrofuran and methanol (V/V=1/2), Raney nickel (50 mg) was addedand reacted for 12 hours at room temperature under the protection ofhydrogen. The reaction solution was filtered, and concentrated underreduced pressure, the resulting residue was purified by silica gelcolumn chromatography (eluent: A system) to obtain tert-butyl2-(3-amino-4-((tert-butoxycarbonyl)(6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)phenyl)-2,8-diazaspiro[4.5]decane-8-carboxylate3f (85 mg, yellow solid), yield: 98.7%.

Step 6 Tert-butyl2-(3-acrylamido-4-((tert-butoxycarbonyl)(6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)phenyl)-2,8-diazaspiro[4.5]decane-8-carboxylate

Tert-butyl2-(3-amino-4-((tert-butoxycarbonyl)(6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)phenyl)-2,8-diazaspiro[4.5]decane-8-carboxylate3f (85 mg, 0.094 mmol) was dissolved in 10 mL of dichloromethane, thesolution was added with N,N-diisopropylethylamine (36.5 mg, 0.283 mmol)and acryloyl chloride (10 mg, 0.104 mmol) and reacted at roomtemperature for 1 hour. The reaction solution was concentrated underreduced pressure, the resulting residue was purified by silica gelcolumn chromatography (eluent: A system) to obtain tert-butyl2-(3-acrylamido-4-((tert-butoxycarbonyl)(6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)phenyl)-2,8-diazaspiro[4.5]decane-8-carboxylate3g (80 mg, yellow solid), yield: 88.8%.

Step 7N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(2,8-diazaspiro[4.5]decan-2-yl)phenyl)acrylamide

Tert-butyl2-(3-acrylamido-4-((tert-butoxycarbonyl)(6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)phenyl)-2,8-diazaspiro[4.5]decane-8-carboxylate3g (80 mg, 0.084 mmol) was dissolved in 6 mL of dichloromethane, thesolution was added with and 3 mL of trifluoroacetic acid under an icebath, and reacted at room temperature for 12 hours under the protectionof nitrogen. The reaction solution was concentrated under reducedpressure. 20 mL of mixed solution of dichloromethane and methanol(V/V=10/1) was added, washed with saturated sodium bicarbonate solution(10 mL), and the organic phase was concentrated under reduced pressure,and the resulting residue was purified by silica gel thin layerchromatography (eluent: B system) to obtainN-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(2,8-diazaspiro[4.5]decan-2-yl)phenyl)acrylamide3 (17 mg, yellow solid), yield: 31.0%. MS m/z (ESI): 656.8 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (s, 1H), 9.60 (s, 1H), 8.71-8.63 (m,2H), 8.29 (s, 1H), 7.21 (d, J=8.8 Hz, 1H), 6.96 (s, 1H), 6.89 (s, 1H),6.56-6.46 (m, 1H), 6.42 (d, J=8.0 Hz, 1H), 6.2 (d, J=15.6 Hz, 1H), 5.69(d, J=10.0 Hz, 1H), 3.93 (s, 6H), 3.32 (t, J=6.4 Hz, 2H), 3.25-3.16 (m,5H), 3.15-3.05 (m, 4H), 1.93 (t, J=7.2 Hz, 2H), 1.81-1.68 (m, 4H).

Example 4N-(2-((6-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(7-ethyl-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)acrylamide

Step 1 2-Benzyl7-(tert-butyl)-2,7-diazaspiro[3.5]nonane-2,7-dicarboxylate

Tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate 111 (2.0 g, 8.84mmol) was dissolved in 20 mL of dichloromethane, the solution was addedwith benzyl chloroformate (3.06 g, 17.67 mmol) andN,N-diisopropylethylamine (4.57 g, 35.35 mmol), and reacted at roomtemperature for 12 hours. The reaction solution was concentrated underreduced pressure, 20 mL of ethyl acetate was added for dissolution,washed with 1M hydrochloric acid solution (10 mL) and saturated sodiumchloride solution (10 mL) successively. The organic phase wasconcentrated under reduced pressure to obtain 2-Benzyl7-(tert-butyl)-2,7-diazaspiro[3.5]nonane-2,7-dicarboxylate 4a (3.18 g,yellow oil), yield: 100%.

Step 2 Benzyl 2,7-diazaspiro[3.5]nonane-2-carboxylate

2-Benzyl 7-(tert-butyl)-2,7-diazaspiro[3.5]nonane-2,7-dicarboxylate 4a(3.20 g, 8.88 mmol) was dissolved in 20 mL of dichloromethane. Thesolution was added with 10 mL of trifluoroacetic acid and reacted atroom temperature for 4 hours. The reaction solution was concentratedunder reduced pressure, 30 mL of ethyl acetate was added to dissolve thesame, washed with sodium bicarbonate solution (10 mL×2) and saturatedsodium chloride solution (10 mL) successively, the organic phase wasconcentrated under reduced pressure, and the resulting residue waspurified by silica gel column chromatography (eluent: A system) toobtain benzyl 2,7-diazaspiro[3.5]nonane-2-carboxylate 4b (2.30 g,colorless viscous material), yield: 99.6%.

¹H NMR (400 MHz, CDCl₃) δ 9.41 (s, 1H), 7.43-7.29 (m, 5H), 5.09 (s, 2H),3.77 (s, 4H), 3.16-2.96 (m, 4H), 2.09-1.96 (m, 4H).

Step 3 Benzyl 7-ethyl-2,7-diazaspiro[3.5]nonane-2-carboxylate

Benzyl 2,7-diazaspiro[3.5]nonane-2-carboxylate 4b (2.3 g, 8.83 mmol) wasdissolved in 20 mL of methanol, the solution was added with 10 mL ofacetaldehyde, acetic acid (1.50 g, 26.5 mmol) and sodiumcyanoborohydride (2.22 g, 35.34 mmol), reacted at room temperature for12 hours. The reaction solution was concentrated under reduced pressure,20 mL of ethyl acetate and 10 mL of water were added, layered, theaqueous phase was washed with saturated sodium bicarbonate solution (10mL) and saturated sodium chloride solution (10 mL) successively, driedover anhydrous sodium sulfate, filtered, and concentrated under reducedpressure, the resulting residue was purified by silica gel columnchromatography (eluent: B system) to obtain benzyl7-ethyl-2,7-diazaspiro[3.5]nonane-2-carboxylate 4c (2.0 g, colorlessviscous material), yield: 78.4%. ¹H NMR (400 MHz, CDCl₃) δ 7.42-7.31 (m,5H), 5.1 (s, 2H), 3.9-3.7 (m, 4H), 3.58-3.38 (m, 2H), 3.15-3.02 (m, 2H),2.85-2.55 (m, 2H), 2.3-2.06 (m, 4H), 1.39 (t, J=12 Hz, 3H).

Step 4 7-Ethyl-2,7-diazaspiro[3.5]nonane

Benzyl 7-ethyl-2,7-diazaspiro[3.5]nonane-2-carboxylate 4c (2.00 g, 6.94mmol) was dissolved in 20 mL of methanol, palladium on carbon (70 mg),reacted at room temperature for 12 hours under the protection ofhydrogen. The reaction solution was filtered, and the filtrate wasconcentrated under reduced pressure to obtain7-ethyl-2,7-diazaspiro[3.5]nonane 4d (1.0 g, oily material), yield:93.4%.

Step 5 Tert-butyl(4-(7-ethyl-2,7-diazaspiro[3.5]nonan-2-yl)-2-nitrophenyl)carbamate

7-Ethyl-2,7-diazaspiro[3.5]nonane 4d (1.50 g, 4.73 mmol), tert-butyl(4-bromo-2-nitrophenyl)carbamate 1c (1.09 g, 7.09 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (821 mg, 1.42 mmol),tris(dibenzylideneacetone)dipalladium (649 mg, 0.71 mmol) and cesiumcarbonate (4.62 g, 14.19 mmol) were dissolved in 50 mL of toluene andreacted at 110° C. for 4 hours. The reaction solution was cooled to roomtemperature, filtered, and concentrated under reduced pressure, and theresulting residue was purified by silica gel column chromatography(eluent: B system) to obtain tert-butyl(4-(7-ethyl-2,7-diazaspiro[3.5]nonan-2-yl)-2-nitrophenyl)carbamate 4e(1.00 g, red solid), yield: 54.1%.

MS m/z (ESI): 391.0 [M+1]

Step 6 4-(7-Ethyl-2,7-diazaspiro[3.5]nonan-2-yl)-2-nitroaniline

Tert-butyl(4-(7-ethyl-2,7-diazaspiro[3.5]nonan-2-yl)-2-nitrophenyl)carbamate 4e(1.00 g, 2.56 mmol) was dissolved in 10 mL of dichloromethane, 5 mL oftrifluoroacetic acid was added and reacted at room temperature for 4hours. The reaction solution was concentrated under reduced pressure andthe resulting residue was purified by silica gel column chromatography(eluent: B system) to obtain4-(7-ethyl-2,7-diazaspiro[3.5]nonan-2-yl)-2-nitroaniline 4f (680 mg, redsolid), yield: 91.5%.

¹H NMR (400 MHz, CDCl₃) δ 7.11 (s, 1H), 6.76 (d, J=8.8 Hz, 1H),6.73-6.67 (m, 1H), 3.65-3.58 (m, 4H), 3.19-3.03 (m, 4H), 2.72-2.56 (m,2H), 2.45-2.35 (m, 2H), 2.17-2.08 (m, 2H), 1.41 (t, J=5.6 Hz, 3H).

Step 7 Tert-butylN-(2,6-dichloro-3,5-dimethoxy-phenyl)-N-[[6-[4-(7-ethyl-2,7-diazaspiro)[3.5]nonan-2-yl)-2-nitroaniline]pyrimidin-4-yl]-methyl-carbamoyl]carbamate

Tert-butyl(6-chloropyrimidin-4-yl)(methyl)carbamoyl-(2,6-dichloro-3,5-dimethoxyphenyl)carbamate1g (1.00 g, 2.03 mmol),4-(7-ethyl-2,7-diazaspiro[3.5]nonan-2-yl)-2-nitroaniline 4f (650 mg,2.24 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (259 mg,0.447 mmol), tris(dibenzylideneacetone)dipalladium (205 mg, 0.224 mmol)and cesium carbonate (2.65 g, 6.13 mmol) was dissolved in 20 mL oftoluene and reacted at 115° C. for 6 hours. The reaction solution wascooled to room temperature, filtered, and concentrated under reducedpressure, the resulting residue was purified by silica gel columnchromatography (eluent: A system) to obtain tert-butylN-(2,6-dichloro-3,5-dimethoxy-phenyl)-N-[[6-[4-(7-ethyl-2,7-diazaspiro)[3.5]nonan-2-yl)-2-nitroaniline]pyrimidin-4-yl]-methyl-carbamoyl]carbamate4g (800 mg, red solid), yield: 52.9%.

¹H NMR (400 MHz, CDCl₃) δ 9.17 (s, 1H), 8.58 (s, 1H), 8.21 (d, J=9.2 Hz,1H), 7.44 (s, 1H), 7.11 (d, J=2.4 Hz, 1H), 6.77-6.71 (m, 1H), 6.61 (s,1H), 3.95 (s, 6H), 3.71 (s, 4H), 364 (s, 3H), 3.52-2.25 (m, 6H),2.08-1.96 (m, 4H), 1.29-1.25 (m, 3H).

Step 8 Tert-butyl N-[6-[[tert-butoxycarbonyl(2,6-dichloro-3,5-dimethoxy-phenyl)carbamoyl]-methyl-amino]pyrimidin-4-yl-N-[4-(7-ethyl-2,7-diazaspiro[3.5]nonan-2-yl)-2-nitro-phenyl]carbamate

Tert-butylN-(2,6-dichloro-3,5-dimethoxy-phenyl)-N-[[6-[4-(7-ethyl-2,7-diazaspiro)[3.5]nonan-2-yl)-2-nitroaniline]pyrimidin-4-yl]-methyl-carbamoyl]carbamate4g (800 mg, 1.07 mmol) was dissolved in 20 mL of tetrahydrofuran,di-tert-butyl dicarbonate (351 mg, 1.61 mmol), the solution was addedwith 4-dimethylaminopyridine (131 mg, 1.07 mmol), heated to 80° C. andreacted for 1 hour. The reaction solution was concentrated under reducedpressure, the resulting residue was purified by silica gel columnchromatography (eluent: B system) to obtain tert-butylN-[6-[[tert-butoxycarbonyl(2,6-dichloro-3,5-dimethoxy-phenyl)carbamoyl]-methyl-amino]pyrimidin-4-yl-N-[4-(7-ethyl-2,7-diazaspiro[3.5]nonan-2-yl)-2-nitro-phenyl]carbamate4h (850 mg, yellow solid), yield: 93.7%.

MS m/z (ESI): 423.0 [M/2+1]

Step 9 Tert-butyl N-[6-[[tert-butoxycarbonyl(2,6-dichloro-3,5-dimethoxy-phenyl)carbamoyl]-methyl-amino]pyrimidin-4-yl-N-[4-(7-ethyl-2,7-diazaspiro[3.5]nonan-2-yl)-2-amino-phenyl]carbamate

Tert-butyl N-[6-[[tert-butoxycarbonyl(2,6-dichloro-3,5-dimethoxy-phenyl)carbamoyl]-methyl-amino]pyrimidin-4-yl-N-[4-(7-ethyl-2,7-diazaspiro[3.5]nonan-2-yl)-2-nitro-phenyl]carbamate4h (850 mg, 1.01 mmol) was dissolved in 20 mL of methanol, the solutionwas added with Raney nickel (500 mg), and reacted for 20 hours at roomtemperature under the protection of hydrogen. The reaction solution wasfiltered, and concentrated under reduced pressure, the resulting residuewas purified by silica gel column chromatography (eluent: A system) toobtain tert-butyl N-[6-[[tert-butoxycarbonyl(2,6-dichloro-3,5-dimethoxy-phenyl)carbamoyl]-methyl-amino]pyrimidin-4-yl-N-[4-(7-ethyl-2,7-diazaspiro[3.5]nonan-2-yl)-2-amino-phenyl]carbamate4i (210 mg, pale yellow solid), yield: 25.6%.

MS m/z (ESI): 408.0 [M/2+1]

Step 10

Tert-butyl N-[6-[[tert-butoxycarbonyl(2,6-dichloro-3,5-dimethoxy-phenyl)carbamoyl]-methyl-amino]pyrimidin-4-yl-N-[4-(7-ethyl-2,7-diazaspiro[3.5]nonan-2-yl)-2-(prop-2-enoylamino)phenyl]carbamate

Tert-butyl N-[6-[[tert-butoxycarbonyl(2,6-dichloro-3,5-dimethoxy-phenyl)carbamoyl]-methyl-amino]pyrimidin-4-yl-N-[4-(7-ethyl-2,7-diazaspiro[3.5]nonan-2-yl)-2-amino-phenyl]carbamate4i (210 mg, 0.257 mmol) was dissolved in 10 mL of dichloromethane, andN,N-diisopropylethylamine (133 mg, 1.03 mmol), the solution was addedwith acryloyl chloride (46.6 mg, 0.815 mmol) and reacted at roomtemperature for 48 hours. The reaction solution was concentrated underreduced pressure, the resulting residue was purified by silica gelcolumn chromatography (eluent: A system) to obtain tert-butylN-[6-[[tert-butoxycarbonyl(2,6-dichloro-3,5-dimethoxy-phenyl)carbamoyl]-methyl-amino]pyrimidin-4-yl-N-[4-(7-ethyl-2,7-diazaspiro[3.5]nonan-2-yl)-2-(prop-2-enoylamino)phenyl]carbamate4j (120 mg, yellow solid), yield: 53.6%.

MS m/z (ESI): 435.0 [M/2+1]

Step 11N-(2-((6-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(7-ethyl-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)acrylamide

Tert-butyl N-[6-[[tert-butoxycarbonyl(2,6-dichloro-3,5-dimethoxy-phenyl)carbamoyl]-methyl-amino]pyrimidin-4-yl-N-[4-(7-ethyl-2,7-diazaspiro[3.5]nonan-2-yl)-2-(prop-2-enoylamino)phenyl]carbamate4j (120 mg, 0.138 mmol) was dissolved in 10 mL of dichloromethane, thesolution was added with 5 mL of trifluoroacetic acid and reacted at roomtemperature for 14 hours. The reaction solution was concentrated underreduced pressure, 20 mL of a mixed solution of dichloromethane andmethanol (V/V=10/1) was added and washed with a saturated sodiumcarbonate solution (10 mL) and a saturated sodium chloride solution (10mL), the organic phase was concentrated under reduced pressure, theresulting residue was purified by silica gel column chromatography(eluent: B system) to obtainN-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(7-ethyl-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)acrylamide4 (25 mg, yellow solid), yield: 27.1%.

MS m/z (ESI): 668.8 [M+1]

¹H NMR (400 MHz, DMSO-d₆) δ 12.09 (s, 1H), 10.48 (s, 1H), 9.69 (s, 1H),8.87 (s, 1H), 8.30 (s, 1H), 7.23 (d, J=8.8 Hz, 1H), 6.94 (s, 1H), 6.89(s, 1H), 6.63-6.45 (m, 1H), 6.32-6.15 (m, 2H), 5.71 (d, J=10.0 Hz, 1H),3.93 (s, 6H), 3.75-3.55 (m, 4H), 3.48-3.38 (m, 2H), 3.22 (s, 3H),3.25-2.81 (m, 4H), 2.19-1.92 (m, 4H), 1.28-1.19 (m, 3H).

Example 5N-(2-((6-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(4-ethyl-4,7-diazaspiro[2.5]octan-7-yl)phenyl)acrylamide

Step 1 N-(4-Bromo-2-nitrophenyl)acetamide

4-Bromo-2-nitroaniline 1a (6.00 g, 27.65 mmol) was dissolved in 45 mL ofacetic acid, the solution was added with acetic anhydride (2.85 mL,30.41 mmol), heated to 100° C. and reacted for 5 hours. The reactionsolution was added with 100 mL of water, and a solid was precipitated,filtered, and the filter cake was dissolved in 50 mL of dichloromethane,the organic phase was washed with water (20 mL×2), dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure toobtain N-(4-bromo-2-nitrophenyl)acetamide 5a (6.60 g, yellow solid),yield: 92.1%.

MS m/z (ESI): 258.8 [M+1]

Step 2 Tert-butyl7-(4-acetamido-3-nitrophenyl)-4,7-diazaspiro[2.5]octane-4-carboxylate

N-(4-Bromo-2-nitrophenyl)acetamide 5a (1.00 g, 3.86 mmol), tert-butyl4,7-diazaspiro[2.5]octane-4-carboxylate 2a (820 mg, 3.86 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (450 mg, 0.772 mmol),tris(dibenzylideneacetone)dipalladium (350 mg, 0.386 mmol) and cesiumcarbonate (3.77 g, 11.6 mmol) were dissolved in 50 mL of toluene andreacted at 115° C. for 4 hours under the protection of argon. Thereaction solution was cooled to room temperature, filtered, concentratedunder reduced pressure and the resulting residue was purified by silicagel column chromatography (eluent: A system) to obtain tert-butyl7-(4-acetamido-3-nitrophenyl)-4,7-diazaspiro[2.5]octane-4-carboxylate 5b(920 mg, red solid), yield: 61.3%.

¹H NMR (400 MHz, CDCl₃) δ 10.01 (s, 1H), 8.61 (d, J=9.6 Hz, 1H), 7.68(s, 1H), 7.32-7.27 (m, 2H), 3.85-3.65 (m, 2H), 3.31-3.15 (m, 2H), 3.02(s, 2H), 2.27 (s, 3H), 1.49 (s, 9H), 1.14-1.08 (m, 2H), 0.98-0.88 (m,2H).

Step 3 (N-(2-Nitro-4-(4,7-diazaspiro[2.5]octan-7-yl)phenyl)acetamide

Tert-butyl7-(4-acetamido-3-nitrophenyl)-4,7-diazaspiro[2.5]octane-4-carboxylate 5b(720 mg, 2.36 mmol) was dissolved in 10 mL of dichloromethane, thesolution was added with 5 mL of trifluoroacetic acid and reacted at roomtemperature for 4 hours. The reaction solution was concentrated underreduced pressure, dissolved by adding 20 mL of ethyl acetate, layered,the organic phase was washed with saturated sodium carbonate solution(10 mL) and saturated saline solution (10 mL) successively, dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure to obtain(N-(2-nitro-4-(4,7-diazaspiro[2.5]octan-7-yl)phenyl)acetamide 5c (650mg, red solid), yield: 95.0%.

MS m/z (ESI): 291.0 [M+1]

Step 4N-(4-(4-Ethyl-4,7-diazaspiro[2.5]octan-7-yl)-2-nitrophenyl)acetamide

(N-(2-Nitro-4-(4,7-diazaspiro[2.5]octan-7-yl)phenyl)acetamide 5c (600mg, 2.06 mmol) was dissolved in 20 mL methanol, 2 mL of 40%acetaldehyde, acetic acid (250 mg, 4.13 mmol) and sodiumcyanoborohydride (260 mg, 4.13 mmol) were added and reacted for 12 hoursat room temperature. The reaction solution was concentrated underreduced pressure, 20 mL of ethyl acetate was added, the organic phasewas washed with saturated sodium carbonate solution (10 mL×2) andsaturated sodium chloride solution (10 mL) successively, dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure to obtainN-(4-(4-ethyl-4,7-diazaspiro[2.5]octan-7-yl)-2-nitrophenyl)acetamide 5d(660 mg, red solid), yield: 100%.

MS m/z (ESI): 319.0 [M+1]

Step 5 4-(4-Ethyl-4,7-diazaspiro[2.5]octan-7-yl)-2-nitroaniline

N-(4-(4-Ethyl-4,7-diazaspiro[2.5]octan-7-yl)-2-nitrophenyl)acetamide 5d(700 mg, 2.20 mmol) was dissolved in 20 mL of ethanol, the solution wasadded with 4 mL of potassium hydroxide (493.4 mg, 8.79 mmol), heated to90° C. and reacted for 3 hours. The reaction solution was concentratedunder reduced pressure, 20 mL of ethyl acetate and 10 mL were added,layered, the organic phase was washed with saturated sodium chloridesolution (10 mL), dried over anhydrous sodium sulfate, filtered,concentrated under reduced pressure and the resulting residue waspurified by silica gel column chromatography (eluent: B system) toobtain 4-(4-ethyl-4,7-diazaspiro[2.5]octan-7-yl)-2-nitroaniline 5e (6.60g, red solid), yield: 98.8%.

MS m/z (ESI): 277.0 [M+1]

Step 6 Tert-butylN-(2,6-dichloro-3,5-dimethoxy-phenyl)-N-[[6-[4-(8-ethyl-5,8-diazaspiro)[2.5]octan-5-yl)-2-nitroaniline]pyrimidin-4-yl]-methyl-carbamoyl]carbamate

Tert-butyl(6-chloropyrimidin-4-yl)(methyl)carbamoyl-(2,6-dichloro-3,5-dimethoxyphenyl)carbamate1g (1.00 g, 2.03 mmol),4-(4-ethyl-4,7-diazaspiro[2.5]octan-7-yl)-2-nitroaniline 5e (618 mg,2.24 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (235 mg,0.407 mmol), tris(dibenzylideneacetone)dipalladium (186 mg, 0.203 mmol)and cesium carbonate (1.99 g, 6.10 mmol) were dissolved in 30 mLtoluene, the mixture was reacted at 115° C. for 4 hours under theprotection of argon. The reaction solution was cooled to roomtemperature, filtered, and concentrated under reduced pressure, theresulting residue was purified by silica gel column chromatography(eluent: B system) to obtain tert-butylN-(2,6-dichloro-3,5-dimethoxy-phenyl)-N-[[6-[4-(8-ethyl-5,8-diazaspiro)[2.5]octan-5-yl)-2-nitroaniline]pyrimidin-4-yl]-methyl-carbamoyl]carbamate5f (800 mg, red solid), yield: 53.7%.

MS m/z (ESI): 366.0 [M/2+1]

Step 7 Tert-butyl N-[6-[[tert-butoxycarbonyl(2,6-dichloro-3,5-dimethoxy-phenyl)carbamoyl]methyl-amino]pyrimidin-4-yl]-N-[4-(8-ethyl-5,8-diazaspiro[2.5]octan-5-yl)-2-nitro-phenyl]carbamate

Tert-butylN-(2,6-dichloro-3,5-dimethoxy-phenyl)-N-[[6-[4-(8-ethyl-5,8-diazaspiro)[2.5]octan-5-yl)-2-nitroaniline]pyrimidin-4-yl]-methyl-carbamoyl]carbamate5f (800 mg, 1.09 mmol) was dissolved in 20 mL of tetrahydrofuran, thesolution was added with di-tert-butyl dicarbonate (358 mg, 1.64 mmol)and 4-dimethylaminopyridine (134 mg, 1.09 mmol), heated to 80° C. andreacted for 1 hour. The reaction solution was concentrated under reducedpressure and the resulting residue was purified by silica gel columnchromatography (eluent: A system) to obtain tert-butylN-[6-[[tert-butoxycarbonyl(2,6-dichloro-3,5-dimethoxy-phenyl)carbamoyl]methyl-amino]pyrimidin-4-yl]-N-[4-(8-ethyl-5,8-diazaspiro[2.5]octan-5-yl)-2-nitro-phenyl]carbamate5g (850 mg, yellow solid), yield: 93.5%.

MS m/z (ESI): 832.8 [M+1]

Step 8 Tert-butylN-[[6-[2-amino-N-tert-butoxycarbonyl-4-(8-ethyl-5,8-diazaspiro[2.5]octan-5-yl)aniline]pyrimidin-4-yl]methyl-carbamoyl]-N-(2,6-dichloro-3,5-dimethoxy-phenyl)carbamate

Tert-butyl N-[6-[[tert-butoxycarbonyl(2,6-dichloro-3,5-dimethoxy-phenyl)carbamoyl]methyl-amino]pyrimidin-4-yl]-N-[4-(8-ethyl-5,8-diazaspiro[2.5]octan-5-yl)-2-nitro-phenyl]carbamate5g (850 mg, 1.02 mmol) was dissolved in 20 mL of methanol, the solutionwas added with Raney nickel (400 mg), and reacted for 6 hours at roomtemperature under the protection of hydrogen. The reaction solution wasfiltered and concentrated under reduced pressure, and the resultingresidue was purified by silica gel column chromatography (eluent: Asystem) to obtain tert-butylN-[[6-[2-amino-N-tert-butoxycarbonyl-4-(8-ethyl-5,8-diazaspiro[2.5]octan-5-yl)aniline]pyrimidin-4-yl]methyl-carbamoyl]-N-(2,6-dichloro-3,5-dimethoxy-phenyl)carbamate5h (600 mg, yellow solid), yield: 73.2%.

MS m/z (ESI): 401.9 [M/2+1]

Step 9 Tert-butylN-[6-[[tert-butoxycarbonyl(2,6-dichloro-3,5-dimethoxy-phenyl)carbamoyl]methylamino]pyrimidin-4-yl]-N-[4-(8-ethyl-5,8-diazaspiro[2.5]octan-5-yl)-2-(prop-2-enoylamino)phenyl]carbamate

Tert-butylN-[[6-[2-amino-N-tert-butoxycarbonyl-4-(8-ethyl-5,8-diazaspiro[2.5]octane-5-yl)aniline]pyrimidin-4-yl]methyl-carbamoyl]-N-(2,6-dichloro-3,5-dimethoxy-phenyl)carbamate5h (600 mg, 0.748 mmol) was dissolved in 15 mL of dichloromethane, thesolution was added with N,N-diisopropylethylamine (463 mg, 3.73 mmol)and acryloyl chloride (135 mg, 1.50 mmol), and reacted at roomtemperature for 4 hours. The reaction solution was concentrated underreduced pressure and the resulting residue was purified by silica gelcolumn chromatography (eluent: A system) to obtain tert-butylN-[6-[[tert-butoxycarbonyl(2,6-dichloro-3,5-dimethoxy-phenyl)carbamoyl]methylamino]pyrimidin-4-yl]-N-[4-(8-ethyl-5,8-diazaspiro[2.5]octane-5-yl)-2-(prop-2-enoylamino)phenyl]carbamate5i (440 mg, red solid), yield: 68.7%.

MS m/z (ESI): 378.6 [(M-100)/2+1]

Step 10N-(2-((6-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(4-ethyl-4,7-diazaspiro[2.5]octan-7-yl)phenyl)acrylamide

Tert-butyl N-[6-[[tert-butoxycarbonyl(2,6-dichloro-3,5-dimethoxy-phenyl)carbamoyl]methylamino]pyrimidin-4-yl]-N-[4-(8-ethyl-5,8-diazaspiro[2.5]octane-5-yl)-2-(prop-2-enoylamino)phenyl]carbamate5i (440 mg, 0.514 mmol) was dissolved in 15 mL of dichloromethane, thesolution was added with 5 mL of trifluoroacetic acid and reacted at roomtemperature for 12 hours. The reaction solution was concentrated underreduced pressure, 20 mL of ethyl acetate was added, washed withsaturated sodium carbonate solution (20 mL) and saturated sodiumchloride solution (20 mL) successively, dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure, theresulting residue was purified by silica gel thin layer chromatography(eluent: B system) to obtainN-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(4-ethyl-4,7-diazaspiro[2.5]octane-7-yl)phenyl)acrylamide5 (100 mg, white solid), yield: 29.7%.

MS m/z (ESI): 678.8 [M+23]

¹H NMR (400 MHz, CDCL₃) δ 12.53 (s, 1H), 8.39 (s, 1H), 7.79 (s, 1H),6.76-6.66 (m, 1H), 6.53 (s, 1H), 6.62 (d, J=16.0 Hz, 1H), 6.26-6.17 (m,1H), 5.9-5.84 (m, 1H), 5.79 (d, J=10.0 Hz, 1H), 3.92 (s, 6H), 3.8-2.1(m, 11H), 1.69-1.42 (m, 3H), 1.32-1.02 (m, 2H), 0.98-0.6 (m, 2H).

Example 6N-(2-((6-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(7-ethyl-2,7-diazaspiro[4.4]nonan-2-yl)phenyl)acrylamide

Step 1 Tert-butyl7-(4-acetylamino-3-nitrophenyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate

N-(4-Bromo-2-nitrophenyl)acetamide 5a (550 mg, 2.12 mmol), tert-butyl2,7-diazaspiro[4.4]nonane-2-carboxylate 6a (460.5 mg, 2.12 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (246 mg, 0.425 mmol),tris(dibenzylideneacetone)dipalladium (194 mg, 0.212 mmol) and cesiumcarbonate (2.08 g, 6.37 mmol) were dissolved in 20 mL of toluene andreacted at 115° C. for 4 hours under the protection of hydrogen. Thereaction solution was cooled to room temperature, filtered, andconcentrated under reduced pressure, the resulting residue was purifiedby silica gel column chromatography (eluent: A system) to obtaintert-butyl7-(4-acetylamino-3-nitrophenyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate6b (490 mg, red solid), yield: 57.1%.

MS m/z (ESI): 405.0 [M+1]

Step 2 (N-(2-Nitro-4-(2,7-diazaspiro[4.4]nonan-2-yl)phenyl)acetamide

Tert-butyl7-(4-acetylamino-3-nitrophenyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate6b (490 mg, 1.21 mmol) was dissolved in 10 mL of dichloromethane, thesolution was added with 5 mL of trifluoroacetic acid, and reacted atroom temperature for 2 hours. The reaction solution was concentratedunder reduced pressure, dissolved by adding 20 mL of ethyl acetate andconcentrated under reduced pressure to obtain(N-(2-nitro-4-(2,7-diazaspiro[4.4]nonan-2-yl)phenyl)acetamide 6c (368mg, red solid), yield: 100%.

MS m/z (ESI): 305.0 [M+1]

Step 3N-(4-(7-Ethyl-2,7-diazaspiro[4.4]nonan-2-yl)-2-nitrophenyl)acetamide

(N-(2-Nitro-4-(2,7-diazaspiro[4.4]nonan-2-yl)phenyl)acetamide 6c (368mg, 1.21 mmol) was dissolved in 10 mL methanol, the solution was addedwith 2 mL of 40% acetaldehyde, acetic acid (145 mg, 2.42 mmol) andsodium cyanoborohydride (304 mg, 4.84 mmol), and reacted for 12 hours atroom temperature. The reaction solution was concentrated under reducedpressure, 20 mL of ethyl acetate and 10 mL of water were added, layered,the organic phase was washed with saturated sodium carbonate solution(20 mL) and saturated sodium chloride solution (10 mL) successively,dried over anhydrous sodium sulfate, filtered, and concentrated underreduced pressure to obtainN-(4-(7-ethyl-2,7-diazaspiro[4.4]nonan-2-yl)-2-nitrophenyl)acetamide 6d(401 mg, red solid), yield: 100%.

MS m/z (ESI): 333.0 [M+1]

Step 4 4-(7-Ethyl-2,7-diazaspiro[4.4]nonan-2-yl)-2-nitroaniline

N-(4-(7-Ethyl-2,7-diazaspiro[4.4]nonan-2-yl)-2-nitrophenyl)acetamide 6d(401 mg, 2.20 mmol) was dissolved in 20 mL ethanol, the solution wasadded with 4 mL of potassium hydroxide (271 mg, 4.83 mmol), heated to90° C. and reacted for 4 hours. The reaction solution was concentratedunder reduced pressure, 20 mL of ethyl acetate and 10 mL of water wereadded, layered, the aqueous phase was extracted with ethyl acetate (10mL×2), the organic phases were combined and washed with saturated sodiumchloride solution (20 mL), dried over anhydrous sodium sulfate,filtered, concentrated under reduced pressure, the resulting residue waspurified by silica gel column chromatography (eluent: B system) toobtain 4-(7-ethyl-2,7-diazaspiro[4.4]nonan-2-yl)-2-nitroaniline 6e (270mg, red solid), yield: 77.1%.

MS m/z (ESI): 291.0 [M+1]

Step 5 Tert-butylN-(2,6-dichloro-3,5-dimethoxy-phenyl)-N-[[6-[4-(3-ethyl-3,8-diazaspiro)[4.4]nonan-8-yl)-2-nitro-aniline]pyrimidin-4-yl]-methyl-carbamoyl]carbamate

Tert-butyl(6-chloropyrimidin-4-yl)(methyl)carbamoyl-(2,6-dichloro-3,5-dimethoxyphenyl)carbamate1g (400 mg, 0.813 mmol),4-(7-ethyl-2,7-diazaspiro[4.4]nonan-2-yl)-2-nitroaniline 6e (260 mg,0.895 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (94 mg,0.163 mmol), tris(dibenzylideneacetone)dipalladium (75 mg, 0.0813 mmol)and cesium carbonate (795 mg, 2.44 mmol) were dissolved in 20 mL oftoluene, the mixture was reacted at 115° C. for 4 hours under theprotection of argon. The reaction solution was cooled to roomtemperature, filtered, and concentrated under reduced pressure, theresulting residue was purified by silica gel column chromatography(eluent: B system) to obtain tert-butylN-(2,6-dichloro-3,5-dimethoxy-phenyl)-N-[[6-[4-(3-ethyl-3,8-diazaspiro)[4.4]nonan-8-yl)-2-nitroaniline]pyrimidin-4-yl]-methyl-carbamoyl]carbamate6f (400 mg, red solid), yield: 66.0%.

MS m/z (ESI): 323.0 [M/2+1]

Step 6 Tert-butylN-[6-[[tert-butoxycarbonyl(2,6-dichloro-3,5-dimethoxy-phenyl)carbamoyl]methyl-amino]pyrimidin-4-yl]-N-[4-(3-ethyl-3,8-diazaspiro[4.4]nonan-8-yl)-2-nitro-phenyl]carbamate

Tert-butylN-(2,6-dichloro-3,5-dimethoxy-phenyl)-N-[[6-[4-(3-ethyl-3,8-diazaspiro)[4.4]nonan-8-yl)-2-nitroaniline]pyrimidin-4-yl]-methyl-carbamoyl]carbamate6f (400 mg, 0.536 mmol) was dissolved in 15 mL of tetrahydrofuran, thesolution was added with di-tert-butyl dicarbonate (175 mg, 0.805 mmol)and 4-dimethylaminopyridine (66 mg, 0.576 mmol), heated to 80° C. andreacted for 1 hour. The reaction solution was concentrated under reducedpressure, the resulting residue was purified by silica gel columnchromatography (eluent: A system) to obtain tert-butylN-[6-[[tert-butoxycarbonyl(2,6-dichloro-3,5-dimethoxy-phenyl)carbamoyl]methyl-amino]pyrimidin-4-yl]-N-[4-(3-ethyl-3,8-diazaspiro[4.4]nonan-8-yl)-2-nitro-phenyl]carbamate6g (410 mg, yellow solid), yield: 90.5%.

Step 7 Tert-butylN-[[6-[2-amino-N-tert-butoxycarbonyl-4-(3-ethyl-3,8-diazaspiro[4.4]nonan-8-yl)aniline]pyrimidin-4-yl]-methyl-carbamoyl]-N-(2,6-dichloro-3,5-dimethoxy-phenyl)carbamate

Tert-butyl N-[6-[[tert-butoxycarbonyl(2,6-dichloro-3,5-dimethoxy-phenyl)carbamoyl]methyl-amino]pyrimidin-4-yl]-N-[4-(3-ethyl-3,8-diazaspiro[4.4]nonan-8-yl)-2-nitro-phenyl]carbamate6g (450 mg, 0.532 mmol) was dissolved in 15 mL of methanol, the solutionwas added with Raney nickel (200 mg), and reacted for 6 hours at roomtemperature under the protection of hydrogen. The reaction solution wasfiltered, concentrated under reduced pressure, the resulting residue waspurified by silica gel column chromatography (eluent: A system) toobtain tert-butylN-[[6-[2-amino-N-tert-butoxycarbonyl-4-(3-ethyl-3,8-diazaspiro[4.4]nonan-8-yl)aniline]pyrimidin-4-yl]-methyl-carbamoyl]-N-(2,6-dichloro-3,5-dimethoxy-phenyl)carbamate6h (310 mg, red solid), yield: 71.4%.

MS m/z (ESI): 408.7 [M/2+1]

Step 8 Tert-butylN-[6-[[tert-butoxycarbonyl(2,6-dichloro-3,5-dimethoxy-phenyl)carbamoyl]methylamino]pyrimidin-4-yl]-N-[4-(3-ethyl-3,8-diazaspiro[4.4]nonan-8-yl)-2-(prop-2-enoylamino)phenyl]carbamate

Tert-butylN-[[6-[2-amino-N-tert-butoxycarbonyl-4-(3-ethyl-3,8-diazaspiro[4.4]nonan-8-yl)aniline]pyrimidin-4-yl]-methyl-carbamoyl]-N-(2,6-dichloro-3,5-dimethoxy-phenyl)carbamate6h (310 mg, 0.380 mmol) was dissolved in 10 mL of dichloromethane, thesolution was added with N,N-diisopropylethylamine (246 mg, 1.90 mmol)and acryloyl chloride (69 mg, 0.760 mmol) and reacted at roomtemperature for 4 hours. The reaction solution was concentrated underreduced pressure, the resulting residue was purified by silica gelcolumn chromatography (eluent: A system) to obtain tert-butylN-[6-[[tert-butoxycarbonyl(2,6-dichloro-3,5-dimethoxyphenyl)carbamoyl]methylamino]pyrimidin-4-yl]-N-[4-(3-ethyl-3,8-diazaspiro[4.4]nonan-8-yl)-2-(prop-2-enoylamino)phenyl]carbamate6i (150 mg, red solid), yield: 45.5%.

MS m/z (ESI): 385.9 [M+1/2]

Step 9N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(7-ethyl-2,7-diazaspiro[4.4]nonan-2-yl)phenyl)acrylamide

Tert-butyl N-[6-[[tert-butoxycarbonyl(2,6-dichloro-3,5-dimethoxy-phenyl)carbamoyl]methylamino]pyrimidin-4-yl]-N-[4-(3-ethyl-3,8-diazaspiro[4.4]nonan-8-yl)-2-(prop-2-enoylamino)phenyl]carbamate6i (150 mg, 0.172 mmol) was dissolved in 10 mL of dichloromethane, thesolution was added with 5 mL of trifluoroacetic acid and reacted at roomtemperature for 12 hours. The reaction solution was concentrated underreduced pressure, 20 mL of ethyl acetate was added, washed withsaturated sodium carbonate solution (10 mL×2) and saturated sodiumchloride solution (10 mL) successively, dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure, theresulting residue was purified by silica gel thin layer chromatography(eluent: B system) to obtainN-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(7-ethyl-2,7-diazaspiro[4.4]nonan-2-yl)phenyl)acrylamide6 (20 mg, white solid), yield: 17.3%.

MS m/z (ESI): 335.8 [M/2+1]

¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (s, 1H), 10.43-10.19 (m, 1H), 9.55 (s,1H), 8.69 (s, 1H), 8.1 (s, 1H), 7.21 (d, J=8.8 Hz, 1H), 7.09-6.94 (m,1H), 6.89 (s, 1H), 6.58-6.44 (m, 1H), 6.42-6.34 (m, 1H), 6.28-6.18 (m,1H), 5.74-5.66 (m, 1H), 3.93 (s, 6H), 3.8-3.46 (m, 2H), 3.38-3.28 (m,4H), 3.24-3.92 (m, 7H), 2.22-1.78 (m, 4H), 1.32-1.12 (m, 3H).

Example 7N-(2-((6-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(4-(dimethylamino)piperidin-1-yl)phenyl)acrylamide

Step 1 N-(4-(4-(Dimethylamino)piperidin-1-yl)-2-nitrophenyl)acetamide

N-(4-Bromo-2-nitrophenyl)acetamide 5a (14.17 g, 49.72 mmol),N,N-dimethylpiperidin-4-amine dihydrochloride 7a (10.00) g, 54.69 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11.5 g, 19.88 mmol),tris(dibenzylideneacetone)dipalladium (9.1 g, 9.94 mmol) and cesiumcarbonate (48.40 g, 148.6 mmol) were dissolved in 150 mL of tolueneunder the protection of nitrogen, and heated to reflux for 4 hours. Thereaction solution was cooled to room temperature, filtered, andconcentrated under reduced pressure, the resulting residue was purifiedby silica gel column chromatography (eluent: B system) to obtainN-(4-(4-(dimethylamino)piperidin-1-yl)-2-nitrophenyl)acetamide 7b (6.40g, brownish black solid), yield: 42%.

MS m/z (ESI): 307.0 [M+1]

Step 2 1-(4-Amino-3-nitrophenyl)-N,N-dimethylpiperidin-4-amine

N-(4-(4-(Dimethylamino)piperidin-1-yl)-2-nitrophenyl)acetamide 7b (6.40g, 20.89 mmol) and potassium hydroxide (5.86 g, 104.4 mmol) weredissolved in 80 mL of a mixed solvent of methanol and water (V/V=1/1),and heated to reflux for 2 hours. The reaction solution was concentratedunder reduced pressure, 100 mL of water were added, extracted with ethylacetate (50 mL×3), the organic phases were combined and washed withwater (50 mL×3) and saturated saline solution (50 mL) successively,dried over anhydrous sodium sulfate, filtered, and concentrated underreduced pressure, the resulting residue was purified by silica gelcolumn chromatography (eluent: B system) to obtain1-(4-amino-3-nitrophenyl)-N,N-dimethylpiperidin-4-amine 7c (5.4 g,brownish black solid), yield: 97.8%.

MS m/z (ESI): 265.0 [M+1]

Step 3 Tert-butyl N-(2,6-dichloro-3,5-dimethoxy-phenyl)-N-[[6-[4-[4-(dimethyl amino)-1-piperidinyl]-2-nitro-anilino]-methyl-carbamoyl]carbamate

Tert-butyl(6-chloropyrimidin-4-yl)(methyl)carbamoyl-(2,6-dichloro-3,5-dimethoxyphenyl)carbamate1g (500 mg, 1.02 mmol),1-(4-amino-3-nitrophenyl)-N,N-dimethylpiperidin-4-amine 7c (285.07 mg,1.02 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (117.66 mg,0.203 mmol), tris(dibenzylideneacetone)dipalladium (93.11 mg, 0.101mmol) and cesium carbonate (662.57 mg, 2.03 mmol) were dissolved in 15mL of toluene under the protection of argon, heated to 120° C. andreacted for 4 hours. The reaction solution was concentrated underreduced pressure and the resulting residue was purified by silica gelcolumn chromatography (eluent: B system) to obtain tert-butylN-(2,6-dichloro-3,5-dimethoxy-phenyl)-N-[[6-[4-[4-(dimethylamino)-1-piperidinyl]-2-nitro-anilino]-methyl-carbamoyl]carbamate 7d(420 Mg, brownish red solid), yield: 57.4%.

MS m/z (ESI): 718.8 [M+1]

Step 4 Tert-butylN-[6-[[tert-butoxycarbonyl-2,6-dichloro-3,5-dimethoxy-phenyl)carbamoyl]-methyl-amino]pyrimidin-4-yl]-N-[4-[4-(dimethylamino)-1-piperidinyl]-2-nitro-phenyl]carbamate

Tert-butyl N-(2,6-dichloro-3,5-dimethoxy-phenyl)-N-[[6-[4-[4-(dim ethylamino)-1-piperidinyl]-2-nitro-anilino]-methyl-carbamoyl]carbamate 7d(400 mg, 0.536 mmol) was dissolved in 20 mL of tetrahydrofuran, thesolution was added with di-tert-butyl dicarbonate (242.63 mg, 1.11 mmol)and 4-dimethylaminopyridine (20.37 mg, 0.167 mmol), and heated to 75° C.and reacted for 2 hours. The reaction solution was concentrated underreduced pressure and the resulting residue was purified by silica gelcolumn chromatography (eluent: B system) to obtain tert-butylN-[6-[[tert-butoxycarbonyl-2,6-dichloro-3,5-dimethoxy-phenyl)carbamoyl]-methyl-amino]pyrimidin-4-yl]-N-[4-[4-(dimethylamino)-1-piperidinyl]-2-nitro-phenyl]carbamate7e (323 mg, orange-yellow solid), yield: 70.9%.

MS m/z (ESI): 818.8 [M+1]

Step 5 Tert-butylN-[[6-[2-amino-N-tert-butoxycarbonyl-4-[4-(dimethylamino)-1-piperidinyl]anilino]pyrimidin-4-yl]methylcarbamoyl]-N-2,6-dichloro-3,5-dimethoxy-phenyl)carbamate

Tert-butylN-[6-[[tert-butoxycarbonyl-2,6-dichloro-3,5-dimethoxy-phenyl)carbamoyl]-methyl-amino]pyrimidin-4-yl]-N-[4-[4-(dimethylamino)-1-piperidinyl]-2-nitro-phenyl]carbamate7e (322 mg, 0.393 mmol) was dissolved in 10 mL methanol, the solutionwas added with Raney nickel (300 mg) and reacted for 3 hours at roomtemperature under the protection of hydrogen. The reaction solution wasfiltered, and concentrated under reduced pressure, the resulting residuewas purified by silica gel column chromatography (eluent: B system) toobtain tert-butylN-[[6-[2-amino-N-tert-butoxycarbonyl-4-[4-(dimethylamino)-1-piperidinyl]anilino]pyrimidin-4-yl]methylcarbamoyl]-N-2,6-dichloro-3,5-dimethoxy-phenyl)carbamate7f (202 mg, yellow solid), yield: 65.1%.

MS m/z (ESI): 788.8 [M+1]

Step 6 Tert-butylN-[[6-[2-acrylamido-N-tert-butoxycarbonyl-4-[4-(dimethylamino)-1-piperidinyl]anilino]pyrimidin-4-yl]methylcarbamoyl]-N-2,6-dichloro-3,5-dimethoxy-phenyl)carbamate

Tert-butylN-[[6-[2-amino-N-tert-butoxycarbonyl-4-[4-(dimethylamino)-1-piperidinyl]anilino]pyrimidin-4-yl]methylcarbamoyl]-N-2,6-dichloro-3,5-dimethoxy-phenyl)carbamate7f (188 mg, 0.238 mmol) was dissolved in 10 mL dichloromethane, thesolution was added with N,N-diisopropylethylamine (131.42 mg, 0.952mmol) and acryloyl chloride (43.09 mg, 0.476 mmol), and reacted at roomtemperature for 2 hours. The reaction solution was concentrated underreduced pressure, the resulting residue was purified by silica gelcolumn chromatography (eluent: B system) to obtain tert-butylN-[[6-[2-acrylamido-N-tert-butoxycarbonyl-4-[4-(dimethylamino)-1-piperidinyl]anilino]pyrimidin-4-yl]methylcarbamoyl]-N-2,6-dichloro-3,5-dimethoxy-phenyl)carbamate7g (162 mg, pale yellow solid), yield: 80.6%. MS m/z (ESI): 842.8 [M+1]

Step 7N-(2-((6-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(4-(dimethylamino)piperidin-1-yl)phenyl)acrylamide

Tert-butylN-[[6-[2-acrylamido-N-tert-butoxycarbonyl-4-[4-(dimethylamino)-1-piperidinyl]anilino]pyrimidin-4-yl]methylcarbamoyl]-N-2,6-dichloro-3,5-dimethoxy-phenyl)carbamate7g (162 mg, 0.192 mmol) was dissolved in 5 mL of dichloromethane, thesolution was added with 5 mL of trifluoroacetic acid, and reacted atroom temperature for 1 hour. The reaction solution was concentratedunder reduced pressure, 10 mL of dichloromethane was added, washed withsaturated sodium carbonate solution (10 mL×2), concentrated underreduced pressure, the resulting residue was purified by silica gelcolumn chromatography (eluent: B system) to obtainN-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(4-(dimethylamino)piperidin-1-yl)phenyl)acrylamide7 (66 mg, pale yellow solid), yield: 53.4%.

MS m/z (ESI): 642.8 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 12.56 (s, 1H), 8.37 (s, 1H), 8.10 (s, 1H),7.64 (s, 1H), 7.23 (d, J=8.9 Hz, 2H), 6.77 (s, 1H), 6.51 (s, 1H), 6.41(d, J=16.5 Hz, 1H), 6.24 (d, J=10.2 Hz, 1H), 5.93 (s, 1H), 5.76 (d,J=9.8 Hz, 1H), 3.91 (s, 6H), 3.80 (d, J=12.1 Hz, 2H), 3.28 (s, 3H), 2.76(s, 3H), 2.56 (s, 6H), 2.01 (s, 2H), 1.74 (s, 2H).

Example 8N-(5-(4-Cyclopropylpiperazin-1-yl)-2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)phenyl)acrylamide

Step 1 N-(4-(4-Cyclopropylpiperazin-1-yl)-2-nitrophenyl)acetamide

N-(4-Bromo-2-nitrophenyl)acetamide 5a (1.00 g, 3.86 mmol),1-cyclopropylpiperazine 8a (483.26 mg, 3.86 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (446.71 mg, 0.772 mmol),tris(dibenzylideneacetone)dipalladium (353.48 mg, 0.386 mmol) and cesiumcarbonate (2.52 g, 7.72 mmol) were dissolved in 10 mL of toluene underthe protection of argon, the solution was heated to 120° C. and reactedfor 4 hours. The reaction solution was cooled to room temperature,concentrated under reduced pressure, and the resulting residue waspurified by silica gel column chromatography (eluent: B system) toobtain N-(4-(4-cyclopropylpiperazin-1-yl)-2-nitrophenyl) acetamide 8b(500 mg, red solid), yield: 42.7%.

MS m/z (ESI): 304.9 [M+1]

Step 2 4-(4-Cyclopropylpiperazin-1-yl)-2-nitroaniline

N-(4-(4-Cyclopropylpiperazin-1-yl)-2-nitrophenyl)acetamide 8b (424 mg,1.39 mmol) was dissolved in 50 mL of a mixed solvent of ethanol andwater (V/V=3/2), heated to 95° C. and reacted for 4 hours. The reactionsolution was concentrated under reduced pressure, extracted withdichloromethane (20 mL×3), the organic phases were combined,concentrated under reduced pressure, the resulting residue was purifiedby silica gel column chromatography (eluent: B system) to obtain4-(4-cyclopropylpiperazin-1-yl)-2-nitroaniline 8c (311 mg, reddish brownsolid), yield: 85.2%.

MS m/z (ESI): 263.0 [M+1]

Step 3 Tert-butylN-[[6-[4-(4-cyclopropylpiperazin-1-yl)-2-nitro-anilino]pyrimidin-4-yl]methylcarbamoyl]-N-(2,6-dichloro-3,5-dimethoxy-phenyl)carbamate

Tert-butyl(6-chloropyrimidin-4-yl)(methyl)carbamoyl-(2,6-dichloro-3,5-dimethoxyphenyl)carbamate1g (500 mg, 1.02 mmol), 4-(4-cyclopropylpiperazin-1-yl)-2-nitroaniline8c (266.71 mg, 1.02 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (117.66 mg, 0.203 mmol),tris(dibenzylideneacetone)dipalladium (93.11 mg, 0.102 mmol) and cesiumcarbonate (662.57 mg, 2.03 mmol) were dissolved in 20 mL of tolueneunder the protection of argon, the mixture was heated to 120° C. andreacted for 4 hours. The reaction solution was cooled to roomtemperature, and concentrated under reduced pressure, the resultingresidue was purified by silica gel column chromatography (eluent: Bsystem) to obtain tert-butylN-[[6-[4-(4-cyclopropylpiperazin-1-yl)-2-nitroanilino]pyrimidin-4-yl]methylcarbamoyl]-N-(2,6-dichloro-3,5-dimethoxy-phenyl)carbamate8d (612 mg, reddish brown solid), yield: 83.9%.

MS m/z (ESI): 716.8 [M+1]

Step 4 Tert-butylN-[[6-[N-tert-butoxycarbonyl-4-(4-cyclopropylpiperazin-1-yl)-2-nitro-anilino]pyrimidin-4-yl]-methylcarbamoyl]-N-2,6-dichloro-3,5-dimethoxy-phenyl)carbamate

Tert-butylN-[[6-[4-(4-cyclopropylpiperazin-1-yl)-2-nitroanilino]pyrimidin-4-yl]methylcarbamoyl]-N-(2,6-dichloro-3,5-dimethoxy-phenyl)carbamate8d (612 mg, 0.853 mmol) was dissolved in 20 mL of tetrahydrofuran,di-tert-butyl dicarbonate (372.26 mg, 1.71 mmol) and4-dimethylaminopyridine (52.09 mg, 0.426 mmol) were added, the reactionsolution was heated to 75° C. and reacted for 2 hours. The reactionsolution was concentrated under reduced pressure, the resulting residuewas purified by silica gel column chromatography (eluent: B system) toobtain tert-butylN-[[6-[N-tert-butoxycarbonyl-4-(4-cyclopropylpiperazin-1-yl)-2-nitro-anilino]pyrimidin-4-yl]-methylcarbamoyl]-N-2,6-dichloro-3,5-dimethoxy-phenyl)carbamate8e (655 mg, orange-yellow solid), yield: 93.9%.

MS m/z (ESI): 816.8 [M+1]

Step 5 Tert-butylN-[[6-[2-amino-N-tert-butoxycarbonyl-4-(4-cyclopropylpiperazin-1-yl)anilino]pyrimidin-4-yl]-methyl-carbamoyl]-N-2,6-dichloro-3,5-dimethoxy-phenyl)carbamate

Tert-butylN-[[6-[N-tert-butoxycarbonyl-4-(4-cyclopropylpiperazin-1-yl)-2-nitro-anilino]pyrimidin-4-yl]-methylcarbamoyl]-N-2,6-dichloro-3,5-dimethoxy-phenyl)carbamate8e (650 mg, 0.795 mmol) was dissolved in 20 mL of methanol, the solutionwas added with Raney nickel (1.00 g), reacted at room temperature for 2hours under a hydrogen atmosphere. The reaction solution was filteredand concentrated under reduced pressure to obtain a crude product oftert-butylN-[[6-[2-amino-N-tert-butoxycarbonyl-4-(4-cyclopropylpiperazin-1-yl)anilino]pyrimidin-4-yl]-methyl-carbamoyl]-N-2,6-dichloro-3,5-dimethoxy-phenyl)carbamate8f (596 mg, orange-yellow solid), yield: 95.2%.

Step 6 Tert-butylN-[[6-[2-acrylamido-N-tert-butoxycarbonyl-4-(4-cyclopropylpiperazin-1-yl)anilino]pyrimidin-4-yl]-methyl-carbamoyl]-N-2,6-dichloro-3,5-dimethoxy-phenyl)carbamate

Tert-butylN-[[6-[2-amino-N-tert-butoxycarbonyl-4-(4-cyclopropylpiperazin-1-yl)anilino]pyrimidin-4-yl]-methyl-carbamoyl]-N-2,6-dichloro-3,5-dimethoxy-phenyl)carbamate8f (565 mg, 0.717 mmol) was dissolved in 10 mL of dichloromethane, thesolution was added with N,N-diisopropylethylamine (411.04 mg, 2.87 mmol)and acryloyl chloride (129.83 mg, 1.43 mmol) and reacted at roomtemperature for 10 minutes. 10 mL of a saturated sodiumhydrogencarbonate solution was added to the reaction solution, extractedwith dichloromethane (20 mL×3), and the organic phase was combined andconcentrated under reduced pressure to obtain crude product oftert-butylN-[[6-[2-acrylamido-N-tert-butoxycarbonyl-4-(4-cyclopropylpiperazin-1-yl)anilino]pyrimidin-4-yl]-methyl-carbamoyl]-N-2,6-dichloro-3,5-dimethoxy-phenyl)carbamate8g (600 mg, yellow solid), yield: 99.5%.

MS m/z (ESI): 842.8 [M+1]

Step 7N-(5-(4-Cyclopropylpiperazin-1-yl)-2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)phenyl)acrylamide

Tert-butylN-[[6-[2-acrylamido-N-tert-butoxycarbonyl-4-(4-cyclopropylpiperazin-1-yl)anilino]pyrimidin-4-yl]-methyl-carbamoyl]-N-2,6-dichloro-3,5-dimethoxy-phenyl)carbamate8g (600 mg, 0.713 mmol) was dissolved in 5 mL of dichloromethane, thesolution was added with 5 mL of trifluoroacetic acid was added, andreacted at room temperature for 4 hours. The reaction solution wasconcentrated under reduced pressure, 10 mL of saturated sodiumbicarbonate solution and 10 mL of dichloromethane were added, layered,the aqueous phase was extracted with dichloromethane (10 mL×2), theorganic phases were combined and concentrated under reduced pressure,the resulting residue was purified by silica gel thin layerchromatography (eluent: B system) to obtainN-(5-(4-cyclopropylpiperazin-1-yl)-2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)phenyl)acrylamide8 (200 mg, pale yellow solid), yield: 43.9%.

MS m/z (ESI): 640.8 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 12.55 (s, 1H), 8.38 (s, 1H), 7.71 (s, 2H),7.21 (d, J=8.8 Hz, 1H), 6.76 (d, J=8.8 Hz, 2H), 6.52 (s, 1H), 6.42 (d,J=17.0 Hz, 1H), 6.21 (dd, J=16.8, 10.0 Hz, 1H), 5.86 (s, 1H), 5.77 (d,J=10.3 Hz, 1H), 3.92 (s, 6H), 3.27 (s, 7H), 2.80 (s, 4H), 1.62 (s, 1H),0.51 (s, 4H).

Example 9N-(5-(4-(Cyclopropyl(methyl)amino)piperidin-1-yl)-2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)-4-yl)amino)phenyl)acrylamide

Step 1 Tert-butyl 4-oxopiperidine-1-carboxylate

Piperidin-4-one hydrochloride 9a (5.0 g, 36.8 mmol) was dissolved in 100mL of tetrahydrofuran, triethylamine (7.7 mL, 55.2 mmol) was added,stirred for 5 min, and di-tert-butyl dicarbonate (9.6 g, 44.2 mmol) and4-dimethylaminopyridine (225 mg, 1.84 mmol) were added, reacted at roomtemperature for 12 hours. The reaction solution was concentrated underreduced pressure, 100 mL of dichloromethane was added, washed with 1Mhydrochloric acid solution (50 mL×2), saturated sodium carbonatesolution (50 mL) and saturated sodium chloride solution (50 mL)successively, dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure to obtain tert-butyl4-oxopiperidine-1-carboxylate 9b (6.7 g, colorless solid), yield: 91.8%.

¹H NMR (400 MHz, CDCl₃) δ 3.71-3.74 (m, 4H), 2.43-2.46 (m, 4H), 1.50 (s,9H)

Step 2 Tert-butyl 4-(cyclopropylamino)piperidine-1-carboxylate

Tert-butyl 4-oxopiperidine-1-carboxylate 9b (12.0 g, 60.2 mmol) wasdissolved in 40 mL of ethanol, 40 mL of glacial acetic acid andcyclopropylamine 9c (4.2 mL, 60.2 mmol) were added and stirred for 0.5hour, sodium cyanoborohydride (7.56 g, 120.4 mmol) was added and reactedat room temperature for 2 hours. The reaction solution was concentratedunder reduced pressure, 500 mL of saturated ammonium chloride solutionwas added, extracted with ethyl acetate (500 mL), washed with saturatedsodium carbonate solution (400 mL) and saturated sodium chloridesolution (500 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure to obtain tert-butyl4-(cyclopropylamino)piperidine-1-carboxylate 9d (11.1 g, colorlessliquid), yield: 77.1%.

¹H NMR (400 MHz, CDCl₃) δ 4.01-4.06 (m, 2H), 2.75-2.83 (m, 3H),2.14-2.17 (m, 1H), 1.90-1.94 (m, 2H), 1.45 (s, 9H), 1.26-1.30 (m, 2H),0.46-0.50 (m, 2H), 0.38-0.40 (m, 2H)

Step 3 Tert-butyl 4-(cyclopropyl(methyl)amino)piperidine-1-carboxylate

Tert-butyl 4-(cyclopropylamino)piperidine-1-carboxylate 9d (11.1 g, 46.2mmol) was dissolved in 300 mL of acetonitrile, and potassium carbonate(19.15 g, 138.6 mmol) and methyl iodide (3.45 mL, 55.44 mmol), reactedat room temperature for 2 hours. The reaction solution was filtered,concentrated under reduced pressure, the resulting residue was purifiedby silica gel column chromatography (eluent: A system) to obtaintert-butyl 4-(cyclopropyl(methyl)amino) piperidine-1-carboxylate 9e (8.0g, colorless liquid), yield: 68%.

¹H NMR (400 MHz, CDCl₃) δ 4.13-4.19 (m, 2H), 2.63-2.69 (m, 3H), 2.39 (s,3H), 1.82-1.99 (m, 3H), 1.47-1.54 (m, 2H), 1.49 (s, 9H), 0.54-0.56 (m,4H)

Step 4 N-Cyclopropyl-N-methylpiperidin-4-amine

Tert-butyl 4-(cyclopropyl(methyl)amino)piperidine-1-carboxylate 9e (8.0g, 31.4 mmol) was dissolved in 30 mL of dichloromethane, 5 mL oftrifluoroacetic acid was added, and reacted at room temperature for 2hours. The reaction solution was concentrated under reduced pressure,the resulting residue was added to 20 mL of dichloromethane andcontinued to concentrate under reduced pressure, and 50 mL ofdichloromethane was added again to dissolve it, and then potassiumcarbonate powder was added until no bubbles were produced, filtered,concentrated under reduced pressure to obtainN-cyclopropyl-N-methylpiperidin-4-amine 9f (3.8 g, brown liquid), yield:78.3%.

¹H NMR (400 MHz, CDCl₃) δ 3.12-3.15 (m, 2H), 2.60-2.63 (m, 2H),2.52-2.56 (m, 1H), 2.34 (s, 3H), 1.85-1.95 (m, 2H), 1.75-1.78 (m, 1H),1.46-1.50 (m, 2H), 0.46-0.50 (m, 2H), 0.40-0.42 (m, 2H)

Step 5N-(4-(4-(Cyclopropyl(methyl)amino)piperidin-1-yl)-2-nitrophenyl)acetamide

N-(4-Bromo-2-nitrophenyl)acetamide 5a (6.18 g, 23.8 mmol),N-cyclopropyl-N-methylpiperidin-4-amine 9f (3.35 g, 21.7 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (2.51 g, 4.34 mmol),tris(dibenzylideneacetone)dipalladium (3.97 g, 4.34 mmol) and cesiumcarbonate (21.2 g, 65.1 mmol) were dissolved in 100 mL of toluene underthe protection of argon, heated to 110° C. and reacted for 4 hours. Thereaction solution was cooled to room temperature, extracted with 500 mLof ethyl acetate, washed with water (300 mL×2) and saturated sodiumchloride solution (300 mL) successively, dried over anhydrous sodiumsulfate, filtered, the filtrate was concentrated under reduced pressure,the resulting residue was purified by silica gel column chromatography(eluent: A system) to obtainN-(4-(4-(cyclopropyl(methyl)amino)piperidin-1-yl)-2-nitrophenyl)acetamide9g (5.0 g, brown solid), yield: 69.4%.

MS m/z (ESI): 333.0 [M+1]

Step 6 1-(4-Amino-3-nitrophenyl)-N-cyclopropyl-N-methylpiperidin-4-amine

N-(4-(4-(Cyclopropyl(methyl)amino)piperidin-1-yl)-2-nitrophenyl)acetamide9g (5.0 g, 15.0 mmol) and potassium hydroxide (8.4 g, 150.0 mmol) wasdissolved in a mixed solution of 320 mL of water and ethanol (V/V=1/15),heated to 90° C. and reacted for 2 hours. The reaction solution wasconcentrated under reduced pressure, 500 mL of ethyl acetate was added,layered, the organic phase was washed with water (400 mL), saturatedsodium chloride solution (400 mL) and saturated sodium carbonatesolution (400 mL), and concentrated under reduced pressure, theresulting residue was purified by silica gel column chromatography(eluent: B system) to obtain1-(4-amino-3-nitrophenyl)-N-cyclopropyl-N-methylpiperidin-4-amine 9h(2.60 g, brown oil), yield: 57.5%. MS m/z (ESI): 291.0 [M+1]

Step 7 Tert-butylN-[[6-[4-[4-[cyclopropyl(methyl)amino)-1-piperidyl]-2-nitro-anilino]pyrimidin-4-yl]methyl-carbamoyl]-N-(2,6-dichloro-3,5-dimethoxy-phenyl)carbamate

Tert-butyl(6-chloropyrimidin-4-yl)(methyl)carbamoyl-(2,6-dichloro-3,5-dimethoxyphenyl)carbamate1g (491.8 mg, 1.00 mmol),1-(4-amino-3-nitrophenyl)-N-cyclopropyl-N-methylpiperidin-4-amine 9h(290.4 mg, 1.00 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene(115.7 mg, 0.20 mmol), tris(dibenzylideneacetone)dipalladium (183.0 mg,0.20 mmol) and cesium carbonate (977 mg, 3.00) were dissolved in 10 mLof toluene under the protection of argon and reacted at 110° C. for 5hours. The reaction solution was cooled to room temperature, filtered,concentrated under reduced pressure, and the resulting residue waspurified by silica gel column chromatography (eluent: B system) toobtain tert-butylN-[[6-[4-[4-[cyclopropyl(methyl)amino)-1-piperidyl]-2-nitroanilino]pyrimidin-4-yl]methylcarbamoyl]-N-(2,6-dichloro-3,5-dimethoxy-phenyl)carbamate9i (310 mg, brown solid), yield: 41.6%.

MS m/z (ESI): 744.8 [M+1]

Step 8 Tert-butylN-[[6-[N-tert-butoxycarbonyl-4-[4-[cyclopropyl(methyl)amino]-1-piperidyl]-2-nitroanilino]pyrimidin-4-yl]methylcarbamoyl]-N-(2,6-dichloro-3,5-dimethoxy-phenyl)carbamate

Tert-butylN-[[6-[4-[4-[cyclopropyl(methyl)amino)-1-piperidyl]-2-nitroanilino]pyrimidin-4-yl]methylcarbamoyl]-N-(2,6-dichloro-3,5-dimethoxy-phenyl)carbamate9i (300 mg, 0.40 mmol) was dissolved in 10 mL of tetrahydrofuran,di-tert-butyl dicarbonate (176 mg, 0.80 mmol) and4-dimethylaminopyridine (48.8 mg, 0.40 mmol) were added, the reactionsolution was heated to 80° C. and reacted for 4 hours. The reactionsolution was concentrated under reduced pressure, and the resultingresidue was purified by silica gel column chromatography (eluent: Bsystem) to obtain tert-butylN-[[6-[N-tert-butoxycarbonyl-4-[4-[cyclopropyl(methyl)amino]-1-piperidyl]-2-nitroanilino]pyrimidin-4-yl]methylcarbamoyl]-N-(2,6-dichloro-3,5-dimethoxy-phenyl)carbamate9j (200 mg, brown solid), yield: 58.1%.

MS m/z (ESI): 846.8 [M+1]

Step 9 Tert-butylN-[[6-[2-amino-N-tert-butoxycarbonyl-4-[4-[cyclopropyl(methyl)amino]-1-piperidyl]anilino]pyrimidin-4-yl]-methyl-carbamoyl]-N-(2,6-dichloro-3,5-dimethoxy-phenyl)carbamate

Tert-butylN-[[6-[N-tert-butoxycarbonyl-4-[4-[cyclopropyl(methyl)amino]-1-piperidyl]-2-nitroanilino]pyrimidin-4-yl]methylcarbamoyl]-N-(2,6-dichloro-3,5-dimethoxy-phenyl)carbamate9j (200 mg, 0.23 mmol) was dissolved in 10 mL of a mixed solvent ofmethanol and tetrahydrofuran (V/V=1/1), the solution was added withRaney nickel (200 mg), and reacted at room temperature for 3 hours undera hydrogen atmosphere. The reaction solution was filtered, concentratedunder reduced pressure, and the resulting residue was purified by silicagel column chromatography (eluent: B system) to obtain tert-butylN-[[6-[2-amino-N-tert-butoxycarbonyl-4-[4-[cyclopropyl(methyl)amino]-1-piperidyl]anilino]pyrimidin-4-yl]-methyl-carbamoyl]-N-(2,6-dichloro-3,5-dimethoxy-phenyl)carbamate9k (90 mg, white solid), yield: 46.6%.

MS m/z (ESI): 817.8 [M+1]

Step 10 Tert-butylN-[[6-[2-acrylamido-N-tert-butoxycarbonyl-4-[4-[cyclopropyl(methyl)amino]-1-piperidinyl]anilino]pyrimidin-4-yl]-methyl-carbamoyl]-N-(2,6-dichloro-3,5-dimethoxy-phenyl)carbamate

Tert-butylN-[[6-[2-amino-N-tert-butoxycarbonyl-4-[4-[cyclopropyl(methyl)amino]-1-piperidinyl]anilino]pyrimidin-4-yl]-methyl-carbamoyl]-N-(2,6-dichloro-3,5-dimethoxy-phenyl)carbamate9k (90 mg, 0.11 mmol) was dissolved in 5 mL of dichloromethane,N,N-diisopropylethylamine (0.1 mL, 0.55 mmol) and acryloyl chloride (20mg, 0.22 mmol) were added under an ice bath, reacted for 1 hour at roomtemperature. 50 mL of dichloromethane was added, layered, the organicphase was washed with saturated sodium carbonate solution (500 mL) andsaturated sodium chloride (50 mL), concentrated under reduced pressure,and the resulting residue was purified by silica gel columnchromatography (eluent: B system) to obtain tert-butylN-[[6-[2-acrylamido-N-tert-butoxycarbonyl-4-[4-[cyclopropyl(methyl)amino]-1-piperidinyl]anilino]pyrimidin-4-yl]-methyl-carbamoyl]-N-(2,6-dichloro-3,5-dimethoxy-phenyl)carbamate91 (70 mg, light yellow solid), yield: 72.9%.

MS m/z (ESI): 869.8 [M+1]

Step 11N-(5-(4-(Cyclopropyl(methyl)amino)piperidin-1-yl)-2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)-4-yl)amino)phenyl)acrylamide

Tert-butylN-[[6-[2-acrylamido-N-tert-butoxycarbonyl-4-[4-[cyclopropyl(methyl)amino]-1-piperidinyl]anilino]pyrimidin-4-yl]-methyl-carbamoyl]-N-(2,6-dichloro-3,5-dimethoxy-phenyl)carbamate9l (68 mg, 0.078 mmol) was dissolved in 2 mL of dichloromethane, thesolution was added with 1 mL of trifluoroacetic acid under an ice bath,and reacted at room temperature for 2 hours. 50 ml of dichloromethanewas added to the reaction solution, and washed with saturated sodiumcarbonate solution (50 mL×2), the organic phase was concentrated underreduced pressure, the resulting residue was purified by silica gel thinlayer chromatography (eluent: B system) to obtainN-(5-(4-(cyclopropyl(methyl)amino)piperidin-1-yl)-2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)-4-yl)amino)phenyl)acrylamide9 (30 mg, pale yellow solid), yield: 57.6%.

MS m/z (ESI): 669.9 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 12.56 (s, 1H), 8.36 (s, 1H), 8.10 (s, 1H),7.67 (s, 1H), 7.24 (m, 1H), 6.76 (d, J=9.0 Hz, 1H), 6.51-6.53 (m, 1H),6.41 (d, J=7.5 Hz, 1H), 6.21-6.27 (m, 1H), 5.95 (s, 1H), 5.76 (d, J=10.4Hz, 1H), 3.91 (s, 6H), 3.74-3.81 (m, 2H), 3.35 (s, 3H), 2.83-2.86 (m,1H), 2.71-2.77 (m, 2H), 2.55 (s, 3H), 2.02-2.10 (m, 3H), 1.80-1.82 (m,2H), 0.85-0.87 (m, 2H), 0.68-0.84 (m, 2H)

Biological Evaluation Test Example 1. Determination of the Effect of theCompounds of the Present Invention Against FGFR Kinase Activity

The following method was used to determine the inhibition degree of thekinase activity of recombinant human FGFR protein by the compounds ofthe present invention under in vitro conditions. Cisbio Company's HTRF®KinEASE-TK tyrosine kinase kit (Cat. No: 62TK0PEB) was used in thepresent method, the kit was used to reflect the inhibitory effect of thecompounds on FGFR kinase activity by determination of thephosphorylation degree of FGFR protein-mediated biotinylated polypeptidesubstrates based on the principle of time-resolved fluorescence energyresonance transfer (TF-FRET). For detailed experimental procedures,refer to the kit instructions. Recombinant human FGFR protein waspurchased from Carna bioscience (Japan, Cat. No: FGFR1 #08-133, FGFR2#08-134, FGFR3 #08-135, and FGFR4 #08-136).

The experimental procedure is briefly described as follows: the testcompound was first dissolved in DMSO to prepare a stock solution, andthen gradiently diluted with the buffer provided in the kit, and thefinal concentration of the test compound in the reaction system rangesfrom 10 μM to 0.1 nM. The concentration of ATP solution (Sangon Biotech(Shanghai) Co., Ltd., A600311) used in the test is the ATP Kmconcentration corresponding to each FGFR subtype measured in advance,and the ATP Km concentration corresponding to FGFR1-4 is 100 μM, 40 μM,40 μM and 120 μM respectively. The reaction was carried out in a384-well microplate, the compound and a certain amount of FGFR proteinwas firstly added to the well, and incubated at room temperature for5-30 minutes, then the ATP solution and the biotinylated polypeptidesubstrate solution were added to the reaction solution, and incubatedfor 50 minutes with shaking at room temperature. Subsequently, ananti-phosphotyrosine antibody coupled with a europium compound andstreptavidin coupled with the modified allophycocyanin XL665 were addedto the reaction, and incubation was continued for 1 hour at roomtemperature with shaking. After the incubation ended, the fluorescenceintensity values of the respective wells at an excitation wavelength of304 nm and emission wavelengths of 620 nM and 665 nM were measured in aTF-FRET mode on a microplate reader. The percentage inhibition of thecompound at each concentration was calculated by comparison with thefluorescence intensity ratio of the control group (0.1% DMSO), and thenonlinear regression analysis was performed on the logarithm values ofthe concentrations of the compounds—inhibition rate by GraphPad Prism 5software to obtain the IC₅₀ value of compounds, see Table 1.

TABLE 1 IC₅₀ data for inhibition of FGFR enzyme activity by thecompounds of the present invention IC₅₀ (nM) Example No. FGFR1 FGFR2FGFR3 FGFR4 The compound of 210 579 575 14 Example 108 of WO2015057938 1160 777 557 5 2 87 189 179 4.6 3 465 2428 715 2 4 382 165 439 1.3 5 624533 989 2.4 6 544 368 731 2.2 7 176 405 729 1.1 8 618 644 880 2.5 9 244228 311 3.8

As can be seen from Table 1, the compounds of the present invention havea better inhibitory effect on FGFR4, and the selectivity is superior toFGFR1, FGFR2 and FGFR3, and the inhibitory activity of the compounds ofthe present invention against FGFR4 is superior to that of the compoundof Example 108 of WO2015057938 (which is prepared and identifiedaccording to Example 108 of WO2015057938).

Test Example 2: Determination of Effect of the Compounds of the PresentInvention Against Hepatocellular Carcinoma Tumor Cell Huh7 Activity

The following method was used to determine the effect of the compoundsof the present invention against tumor cell proliferation. For the FGFR4subtype, hepatocellular carcinoma tumor cells Huh7 (purchased from theCell Resource Center of Shanghai Institutes for Biological Sciences,Chinese Academy of Sciences) were used to determine the inhibitionagainst the activity of hepatocellular carcinoma tumor cells. Huh7 cellswere cultured in a DMEM medium containing 10% of fetal bovine serum, 100U of penicillin and 100 μg/mL of streptomycin. Cultured in an incubatorof 37° C., 5% CO₂. Hepatocellular carcinoma tumor cell activity wasmeasured by using a kit of Cell Counting Kit-8 (Dojindo, DojindoMolecular Technologies, Inc).

The experimental method was carried out according to the steps of thekit instructions, and is briefly described as follows: the test compoundwas first dissolved in DMSO to prepare a stock solution, and thengradiently diluted with the corresponding medium of the cells to preparea test sample, and the final concentration of the compound was in therange of 30 μM to 0.01 nM. Tumor cells in the logarithmic phase wereseeded into 96-well cell culture plates at a suitable density, culturedin an incubator of 37° C., 5% CO₂ overnight, then test compound sampleswere added and continued to culture the cells for 72 hours. Aftercompletion of the culture, a suitable volume of CCK-8 test solution wasadded to each well, and incubated at 37° C. for 1 to 4 hours, and thenthe absorbance values of the respective wells at 450 nM were read on amicroplate reader. The percentage inhibition of the compounds at eachconcentration was calculated by comparison with the absorbance value ofthe control group (0.3% DMSO), and the nonlinear regression analysis wasperformed on the logarithm value of concentrations of thecompounds—inhibition rate by GraphPad Prism 5 software to obtain theIC₅₀ value of compounds, see Table 2.

TABLE 2 IC₅₀ data for inhibition of hepatocellular carcinoma tumor cellsHuh7 activity by the compounds of the present invention Example No.IC₅₀(nM)/Huh7 The compound of 18 Example 108 of WO2015057938 5 12 6 10 74.8

As can be seen from Table 2, the compounds of the present invention havea remarkable proliferation inhibitory effect against FGFR4 abnormalhepatocellular carcinoma tumor cells, and are superior to the compoundof Example 108 of WO2015057938.

Test Example 3: Test of the Growth Inhibitory Effect of the Compounds ofthe Present Invention Against Human Hepatocellular Carcinoma Tumor CellHuh7 Tumor-Bearing BALB/c Nude Mice Xenografts 1. Experiment Objectives

This test was used to evaluate the growth inhibitory effect of thecompound of Example 5 and the compound of Example 108 of WO2015057938 onthe Huh7 tumor-bearing BALB/c nude mice xenografts, administered twicedaily for 22 days, orally or intraperitoneally.

2. Preparation of Test Substances

2.1 Preparation of Dosing Formulation of Vehicle:

A suitable volume of a formulation containing 5% of DMSO, 10% of PEG300, 8% of Tween 80, and 77% of physiological saline (v/v) was preparedas a blank group administration test solution.

2.2 Preparation of Dosing Formulation the Compound of Example 108 ofWO2015057938

An appropriate amount of the compound of Example 108 of WO2015057938 wasweighed and placed in a glass vial; an appropriate volume of DMSO wasadded, followed by vortex and sonication until the drug was completelydissolved, and then an appropriate amount of solvent TPS(Tween80:PEG300:normal saline=8%:10%:77% (v/v/v) solution) was added,followed by vortex and sonication evenly, so that the ratio ofDMSO:PEG300:Tween-80:normal saline was 5:10:8:77 (v/v/v/v), and prepareddosing formulation with a concentration of 2.5 mg/mL.

2.3 Preparation of Intraperitoneal Injection Formulation of the Compoundof Example 5

An appropriate amount of the compound of Example 5 was weighed andplaced in a glass bottle; an appropriate volume of DMSO was added,followed by vortex and sonication until the drug was completelydissolved, and then an appropriate amount of solvent TPS(Tween80:PEG300:normal saline=8%: 10%: 77% (v/v/v) solution) was added,followed by vortex and sonication evenly, so that the ratio ofDMSO:PEG300:Tween-80:normal saline was 5:10:8:77 (v/v/v/v), and prepareddosing formulation with concentrations of 2.5 mg/mL and 5 mg/mL.

2.4 Preparation of Oral Formulation of the Compound of Example 5

600 mg of the compound of Example 5 was weighed and placed in a glassbottle; an appropriate volume of 3.92 mL of EtOH was added, 9.8 mL ofPEG400 was added, and then 5.88 mL of 1 M HCl was added, followed byvortex and sonication evenly so that the ratio of EtOH:PEG400:water was20:50:30 (v/v/v), and prepared dosing formulation with a concentrationof 30 mg/mL.

3. Experimental Animals

Species and strains: 45 of BALB/c nude mice, SPF, female, 7 to 9 weeksold (16 to 22 grams), healthy, adapted to environmental for 5 to 7 days.Certification No.: 1140070017310, purchased from Beijing Vital RiverLaboratory Animal Technology Co., Ltd.

4. Hepatocellular Carcinoma Tumor Cell Huh7 Culture

On day 0, Huh7 cells were cultured in DMEM medium containing 10% offetal bovine serum, 100 U of penicillin, and 100 μg/mL of streptomycin.And cultured in an incubator of 37° C., 5% CO₂. Before inoculation,logarithmic phase cells were taken, digested with 0.25% of trypsin, thenwashed with PBS (Phosphate Buffered Saline, phosphate buffer), the cellswere resuspended in serum-free medium for counting, and the cellconcentration was adjusted to 3.3×10⁷ cells/mL (1:1 Matrigel, PBS).

5. Animal Inoculation and Grouping

Each mouse was inoculated subcutaneously in the right axilla with 150 μLof cell suspension (5.0×10⁶ cells/mouse) under sterile conditions. Onday 12 after inoculation, when the tumor grew to a volume of 200-300mm³, mice with similar tumor volume and good shape were selected (theshape was as single spherical as possible, no irregular shape ormultiple tumors gathered together) and divided into 5 groups, each grouphad 9 mice.

6. Animal Administration and Observation

Each group of animals was administrated (intraperitoneal injection (ip)or oral administration (po)) a test substance twice a day (bid) at a fixtime per day according to the body weight of the animals. The first dosewas administered on the day of grouping (day 13 after inoculation), andcontinued for 22 days, the body weight of the animals was recordeddaily.

Group 1, solvent control group, intraperitoneal injection of formulationof vehicle, bid, administration volume of 10 mL/kg; Group 2,intraperitoneal administration of the compound of Example 108 ofWO2015057938, administered at a dose of 25 mg/kg, twice a day (bid);Groups 3 and 4, intraperitoneal injection of the compound of Example 5at doses of 25 mg/kg and 50 mg/kg respectively, bid; Group 5,intragastric injection of the compound of Example 5 at a dose of 300mg/kg, bid.

The formation of tumor in the inoculated part of each group of animalswas observed. The long diameter (Y) and short diameter (X) of the tumornodules were measured twice a week using vernier calipers and calculatedaccording to the following formula:

Volume of tumor nodules (V): V=(X ² Y)/2.

Evaluation index of antitumor activity: tumor growth inhibition rate TGI(%), relative tumor proliferation rate T/C (%).

The relative tumor volume (RTV) is calculated as:

RTV=100×TV _(t) /TV _(initial)

wherein, TV_(initial) is the tumor volume measured at the time ofgrouping administration; TV_(t) is the tumor volume at each measurementduring administration.

The calculation formula for the relative tumor proliferation rate (%T/C) is:

% T/C=100%×(RTV _(T) /RTV _(C))

wherein, RTV_(T) represents RTV of the treatment group; RTV_(C)represents RTV of the solvent control group.

The calculation formula for the tumor growth inhibition rate TGI (%) is:

TGI=100%×[1−(TV _(t(T)) −TV _(initial(T)))/(TV _(t(C)) −TV_(initial(C)))]

wherein, TV_(t(T)) represents the tumor volume at each measurement inthe treatment group; TV_(initial(T)) represents the tumor volume of thetreatment group at the time of grouping administration; TV_(t(C))represents the tumor volume at each measurement in the solvent controlgroup; TV_(initial(C)) represents the tumor volume of the solventcontrol group at the time of grouping administration.

The calculation formula for the tumor weight inhibition rate IR (%) is:

IR=100%×(W _(C) −W _(T))/W _(C)

wherein, We represents the tumor weight of the control group; W_(T)represents the tumor weight of the treatment group.

The calculation formula for the weight loss rate of animals is (see FIG.3 for the results):

Weight loss rate of animals=100%×(BW _(initial) −BW _(t))/BW _(initial)

wherein, BW_(t) represents the body weight of the animal at eachmeasurement during administration; BW_(initial) represents the bodyweight of the animal at the time of grouping administration.

7. Results

A graph showing changes in mean tumor volume of xenografts ofhepatocellular carcinoma tumor cell Huh7 tumor-bearing BALB/c nude miceby the compound of Example 108 of WO2015057938 and the compound ofExample 5 of the present invention is shown in FIG. 1.

A graph showing changes in mean relative tumor volume of xenografts ofhepatocellular carcinoma tumor cell Huh7 tumor-bearing BALB/c nude miceby the compound of Example 108 of WO2015057938 and the compound ofExample 5 of the present invention is shown in FIG. 2.

A graph showing changes in body weight of hepatocellular carcinoma tumorcell Huh7 tumor-bearing BALB/c nude mice by the compound of Example 108of WO2015057938 and the compound of Example 5 of the present inventionis shown in FIG. 3.

TABLE 3 Growth inhibition rate (TGI %) of the compound of the presentinvention against hepatocellular carcinoma tumor cell Huh7 tumor−bearingBALB/c nude mice xenografts Days after inoculation Tumor growthinhibition rate (TGI %) Day Day Day Day Day Day Group 16 20 23 27 30 34The compound of  34%  21%  21%  29%  24%  16% Example 108 ofWO2015057938 25 mg/kg (IP, bid) The compound of  33%  31%  40%  40%  32% 20% Example 5 25 mg/kg (IP, bid) The compound of  78%  81%  95%  89% 76%  57% Example 5 50 mg/kg (IP, bid) The compound of 147% 172% 153%137% 135% 129% Example 5 300 mg/kg (PO, bid)

TABLE 4 Relative tumor growth rate TIC (%) of the compound of thepresent invention on hepatocellular carcinoma tumor cell Huh7tumor-bearing BALB/c nude mice xenografts Days after inoculationRelative tumor growth rate TIC (%) Day Day Day Day Day Day Day Group 1316 20 23 27 30 34 The compound 100% 91% 90% 87% 81% 83% 87% of Example108 of WO2015057938 25 mg/kg (IP, bid) The compound of 100% 91% 86% 78%76% 79% 85% Example 5 25 mg/kg (IP, bid) The compound 100% 80% 65% 48%44% 49% 60% of Example 5 50 mg/kg (IP, bid) The compound 100% 61% 25%16% 13%     9.4%     9.0% of Example 5 300 mg/kg (PO, bid)

TABLE 5 Tumor weight and tumor weight inhibition rate of each group ofanimals at the end of the experiment Dosage of Tumor weight (g) Tumorweight administration Administration Mean ± standard inhibition Group(mg/kg) method error rate (%) Solvent control — IP, BID 0.9306 ± 0.0924/ The compound of 25 IP, bid 0.9106 ± 0.0583 2.2%  Example 108 ofWO2015057938 The compound of 25 IP, bid 0.8393 ± 0.0602 10% Example 5The compound of 50 IP, bid 0.6473 ± 0.0597 30% Example 5 The compound of300  PO, bid 0.0562 ± 0.0069 94% Example 5

TABLE 6 Body weight and weight loss rate of each group of animals duringdrug administration Days after inoculation Animal body weight ± standarderror (g) or weight loss rate (%) Day Day Day Day Day Day Day Group 1316 20 23 27 30 34 Solvent control g 19.1 ± 0.3 19.2 ± 0.3 19.2 ± 0.419.5 ± 0.4 19.6 ± 0.4 19.8 ± 0.4 20.1 ± 0.4 % 0% −0.64% −0.52% −2.3%−2.9% −3.7% −5.4% The compound of g 18.0 ± 0.3 18.1 ± 0.3 19.2 ± 0.418.3 ± 0.2 18.4 ± 0.3 18.7 ± 0.2 18.9 ± 0.3 Example 108 of % 0% −0.62%−6.7% −2.0% −2.7% −4.2% −5.0% WO2015057938 25 mg/kg (IP, bid) Thecompound g 18.3 ± 0.3 18.9 ± 0.3 18.9 ± 0.3 19.2 ± 0.3 19.4 ± 0.3 19.6 ±0.3 19.9 ± 0.3 of Example 5 % 0%  −3.1%  −3.0% −5.0% −5.8% −7.0% −8.6%25 mg/kg (IP, bid) The compound g 17.5 ± 0.3 18.1 ± 0.3 18.4 ± 0.3 18.6± 0.3 18.7 ± 0.3 19.0 ± 0.4 18.9 ± 0.4 of Example 5 % 0%  −3.2%  −5.0%−6.1% −6.8% −8.0% −7.5% 50 mg/kg (IP, bid) The compound g 18.0 ± 0.317.9 ± 0.3 18.2 ± 0.3 18.8 ± 0.2 19.1 ± 0.3 19.3 ± 0.3 19.8 ± 0.3 ofExample 5 % 0%    0.43% −0.93% −4.4% −6.0% −7.4% −9.9% 300 mg/kg (PO,bid)

It can be seen from Tables 3 to 6 and FIGS. 1 to 3 that at the doses of25 mg/kg (IP, bid), 50 mg/kg (IP, bid) and 300 mg/kg (PO, bid), thecompound of Example 5 of the present invention had a significant growthinhibitory effect against the in vivo tumor model in mice establishedbased on Huh-7 cells within 22 days, and had no significant body weightchange. As can be seen from Tables 3-6, FIGS. 1 and 2, the activity ofthe compound of Example 5 was superior to that of the compound ofExample 108 of WO2015057938 at a dose of 25 mg, IP.

All documents mentioned in the present application are herebyincorporated by reference in their entireties as each document is citedseparately as a reference. It is to be understood that variousmodifications and changes may be made by those skilled in the art afterreading the above teachings of the present invention, these equivalentforms also fall within the scope defined by the claims appended hereto.

1. A method for treating diseases of FGFR4 over-expression, comprisingadministering to a patient in need of treatment an effective amount of acompound represented by formula (I) or a stereoisomer, tautomer thereofor a pharmaceutically acceptable salt thereof:

wherein: each of R¹ is independently selected from alkyl, halogen,alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —NR⁷R⁸, —C(O)NR⁷R⁸,—C(O)R⁹, —C(O)OR⁹ or —NR⁷C(O)R⁸, wherein the alkyl, alkoxy, cycloalkyl,heterocyclyl, aryl or heteroaryl is optionally further substituted byone or more substituents selected from the group consisting of hydroxyl,halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl,heteroaryl, —NR⁷R⁸, —C(O)NR⁷R⁸, —C(O)R⁹, —C(O)OR⁹ and —NR⁷C(O)R⁸; R² isselected from —NR⁴C(O)CR⁵═CHR⁶ or —NR⁴C(O)C≡CR⁵; R³ is aspiroheterocyclyl, wherein the spiroheterocyclyl is optionally furthersubstituted by one or more substituents selected from the groupconsisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy,cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkoxy, —NR⁷R⁸,—C(O)NR⁷R⁸, —C(O)R⁹, —C(O)OR⁹ and —NR⁷C(O)R⁸; each of R⁴ isindependently selected from hydrogen or alkyl, wherein the alkyl isoptionally further substituted by one or more substituents selected fromthe group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy,cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkoxy, —NR⁷R⁸,—C(O)NR⁷R⁸, —C(O)R⁹, —C(O)OR⁹ and —NR⁷C(O)R⁸; R⁵ and R⁶ are eachindependently selected from hydrogen, alkyl or halogen, wherein thealkyl is optionally further substituted by one or more substituentsselected from the group consisting of hydroxy, halogen, nitro, cyano,alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkoxy,—NR⁷R⁸, —C(O)NR⁷R⁸, —C(O)R⁹, —C(O)OR⁹ and —NR⁷C(O)R⁸; R⁷, R⁸ and R⁹ areeach independently selected from hydrogen, alkyl, cycloalkyl,heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl,heterocyclyl, aryl or heteroaryl is optionally further substituted byone or more substituents selected from the group consisting of hydroxy,halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl,heteroaryl, —NR¹⁰R¹¹, —C(O)NR¹⁰R¹¹, —C(O)R¹², —C(O)OR¹² and—NR¹⁰C(O)R¹¹; alternatively, R⁷ and R⁸ together with the N atom to whichthey are attached form a 4 to 8 membered heterocyclyl, wherein the 4 to8 membered heterocyclic ring contains one or more N, O, S(O)_(n) atoms,and the 4 to 8 membered heterocyclic ring is further substituted by oneor more substituents selected from the group consisting of hydroxy,halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl,heteroaryl, ═O, —NR¹⁰R¹¹, —C(O)NR¹⁰R¹¹, —C(O)R¹², —C(O)OR¹² and—NR¹⁰C(O)R¹¹; R¹⁰, R¹¹ and R¹² are each independently selected fromhydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, whereinthe alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are optionallyfurther substituted by one or more substituents selected from the groupconsisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl,heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylate; m is 1,2, 3 or 4; and n is 0, 1, or
 2. 2. The method of claim 1, wherein thecompound is a compound of formula (II):

wherein R¹, R², R³ and m are defined as in formula (I).
 3. The method ofclaim 1, wherein R¹ is selected from halogen or alkoxy.
 4. The method ofclaim 1, wherein R² is —NHC(O)CH═CH₂.
 5. The method of claim 1, whereinR³ is a monospiroheterocyclyl, and the monospiroheterocyclyl isoptionally further substituted by one or more substituents selected fromthe group consisting of alkyl, alkoxy, cycloalkyl, heterocyclyl, aryland heteroaryl.
 6. The method of claim 1, wherein R³ is selected from3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered,4-membered/6-membered, 5-membered-/5-membered or 5-membered/6-memberedmonospiroheterocyclyl, and the monospiroheterocyclyl is optionallyfurther substituted by alkyl.
 7. The method of claim 1, wherein R³ isselected from:

wherein each R¹³ is independently selected from hydrogen, alkyl, alkoxy,cycloalkyl, heterocyclyl, aryl or heteroaryl.
 8. The method of claim 1,wherein the compound is selected from:


9. A method for treating diseases of FGF19 amplification, comprisingadministering to a patient in need of treatment an effective amount of acompound represented by formula (I) or a stereoisomer, tautomer thereofor a pharmaceutically acceptable salt thereof:

wherein: each of R¹ is independently selected from alkyl, halogen,alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —NR⁷R⁸, —C(O)NR⁷R⁸,—C(O)R⁹, —C(O)OR⁹ or —NR⁷C(O)R⁸, wherein the alkyl, alkoxy, cycloalkyl,heterocyclyl, aryl or heteroaryl is optionally further substituted byone or more substituents selected from the group consisting of hydroxyl,halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl,heteroaryl, —NR⁷R⁸, —C(O)NR⁷R⁸, —C(O)R⁹, —C(O)OR⁹ and —NR⁷C(O)R⁸; R² isselected from —NR⁴C(O)CR⁵═CHR⁶ or —NR⁴C(O)C≡CR⁵; R³ is aspiroheterocyclyl, wherein the spiroheterocyclyl is optionally furthersubstituted by one or more substituents selected from the groupconsisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy,cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkoxy, —NR⁷R⁸,—C(O)NR⁷R⁸, —C(O)R⁹, —C(O)OR⁹ and —NR⁷C(O)R⁸; each of R⁴ isindependently selected from hydrogen or alkyl, wherein the alkyl isoptionally further substituted by one or more substituents selected fromthe group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy,cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkoxy, —NR⁷R⁸,—C(O)NR⁷R⁸, —C(O)R⁹, —C(O)OR⁹ and —NR⁷C(O)R⁸; R⁵ and R⁶ are eachindependently selected from hydrogen, alkyl or halogen, wherein thealkyl is optionally further substituted by one or more substituentsselected from the group consisting of hydroxy, halogen, nitro, cyano,alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkoxy,—NR⁷R⁸, —C(O)NR⁷R⁸, —C(O)R⁹, —C(O)OR⁹ and —NR⁷C(O)R⁸; R⁷, R⁸ and R⁹ areeach independently selected from hydrogen, alkyl, cycloalkyl,heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl,heterocyclyl, aryl or heteroaryl is optionally further substituted byone or more substituents selected from the group consisting of hydroxy,halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl,heteroaryl, —NR¹⁰R¹¹, —C(O)NR¹⁰R¹¹, —C(O)R¹², —C(O)OR¹² and—NR¹⁰C(O)R¹¹; alternatively, R⁷ and R⁸ together with the N atom to whichthey are attached form a 4 to 8 membered heterocyclyl, wherein the 4 to8 membered heterocyclic ring contains one or more N, O, S(O)_(n) atoms,and the 4 to 8 membered heterocyclic ring is further substituted by oneor more substituents selected from the group consisting of hydroxy,halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl,heteroaryl, ═O, —NR¹⁰R¹¹, —C(O)NR¹⁰R¹¹, —C(O)R¹², —C(O)OR¹² and—NR¹⁰C(O)R¹¹; R¹⁰, R¹¹ and R¹² are each independently selected fromhydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, whereinthe alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are optionallyfurther substituted by one or more substituents selected from the groupconsisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl,heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylate; m is 1,2, 3 or 4; and n is 0, 1, or
 2. 10. The method of claim 9, wherein thecompound is a compound of formula (II):

wherein R¹, R², R³ and m are defined as in formula (I).
 11. The methodof claim 9, wherein R¹ is selected from halogen or alkoxy.
 12. Themethod of claim 9, wherein R² is —NHC(O)CH═CH₂.
 13. The method of claim9, wherein R³ is a monospiroheterocyclyl, and the monospiroheterocyclylis optionally further substituted by one or more substituents selectedfrom the group consisting of alkyl, alkoxy, cycloalkyl, heterocyclyl,aryl and heteroaryl.
 14. The method of claim 9, wherein R³ is selectedfrom 3-membered/6-membered, 4-membered/4-membered,4-membered/5-membered, 4-membered/6-membered, 5-membered-/5-membered or5-membered/6-membered monospiroheterocyclyl, and themonospiroheterocyclyl is optionally further substituted by alkyl. 15.The method of claim 9, wherein R¹ is selected from halogen or alkoxy; R²is —NHC(O)CH═CH₂; and R³ is selected from:

wherein each R¹³ is independently selected from hydrogen, alkyl, alkoxy,cycloalkyl, heterocyclyl, aryl or heteroaryl.
 16. The method of claim 9,wherein the compound is selected from: